Glutamate and Psychiatry: Glutamate, NMDA Receptors, and Where Are We, and What Does the the Quest for Rapid Antidepressants Future Hold?

Sanjay J. Mathew, MD The story of Professor of Psychiatry and Behavioral Sciences Johnson Family Chair for Research in Psychiatry Menninger Department of Psychiatry and Behavioral Sciences Baylor College of Medicine Staff Physician, Michael E. Debakey VA Medical Center Houston, Texas

Evolution of Antidepressants: Antidepressants 1990s–2015 1950–1980s 1995 2000 19501955 1960 1965 1990

Venlafaxine (1993) Citalopram (1998)

Imipramine (1957) Isocarboxazid (1959) Amitriptyline (1961) Protriptyline (1967) Paroxetine (1992) Nefazodone (1994) Mirtazapine (1996) Phenelzine (1961) Sertraline (1991) Fluvoxamine (OCD – 1994) (EU – 1996)

Clomipramine Desipramine (1964) Tranylcypromine (1969) (EU 1960, US 1989) Doxepin (1969) 2000 2005 2010 2015

19701975 1980 1985

Fluoxetine / Desvenlafaxine Vilazodone (2011) Olanzapine (2003) Selegiline patch (2005) (2008)

Escitalopram (2002) (2013) Nortriptyline (1977) Trazodone (1981) (1989) L-methylfolate (2006) Quetiapine XR Bupropion (1985) Duloxetine (2004) Vortioxetine(2013) (MDD – 2009) Trimipramine (1979) Fluoxetine (1987) Brexpiprazole (2015) Maprotiline (1987) Aripiprazole (MDD – 2007)

Slow Progress in Discovering Novel Drug Targets What are Key Unmet Needs Beyond Serotonin, Norepinephrine, and Dopamine for Antidepressants?

• Rapid onset of activity

• Prevention of relapse

• Impacts suicide risk Distinct Drugs • Low side effect burden Number of Mechanistically

• Addresses underlying pathophysiology

Insel TR, et al. Mol Psychiatry. 2006;11(1):11-17. Tight Physiological Control of Glutamate Neurotransmission and Potential Therapeutic Targets

+ • Most common excitatory amino acid in TCA Cycle CNS • Fundamental to brain bioenergetics and metabolism Group II Voltage • Derived from both neuronal/glial pathways as well as TCA dependent cycle • Distribution of glutamate in compartments – Neurons: 90%–95% – Glia: 5%–10% Extrasynaptic Glu – Blood: 0.02% – Extracellular space: 0.0008% (1/100,000 of total) Group I mGluR

Extrasynaptic NMDA CNS = central nervous system; TCA = tricarboxylic acid. Mason G. Presented at: 71st Annual Meeting of the Society of Biological Psychiatry; May 12-14, 2016: mGluR = metabotropic glutamate ; NMDA = N-methyl-D-aspartate. Atlanta, GA. Sanacora G, et al. Nat Rev Drug Discov. 2008;7(5):426-437. Sanacora G, et al. 2008

Enhancement of Cellular Plasticity May Be Final NMDA Antagonists Show Common Pathway for Antidepressant Treatments Antidepressant-Like Activity in Preclinical Models

Exposure to inescapable shock disrupted hippocampal LTP, a process dependent on NMDA receptor activation

Skolnick hypothesized that pathways subserved by NMDA 5-HT receptors are critical in eliciting behavioral deficits (ie, 1A learned helplessness) induced by inescapable stressors

Attenuation NMDA antagonists found to mitigate behavioral deficits similar to monoamines Exhibit AD-like effects in chronic mild stress model Forced swim and tail suspension tests

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. AD = antidepressant; LTP = long-term potentiation. Mathew SJ, et al. Neuropsychopharmacology. 2008;33(9):2080-2092. Skolnick P, et al. Trends Pharmacol Sci. 2009;30(11):563-569.

Rave drug tested against depression: The Washington Post Companies and clinicians turn to ketamine to treat mental-health disorder as pipeline of new drugs dries up Onetime party drug hailed as miracle for treating severe depression By Sara Solovitch February 1, 2016

www.washingtonpost.com/national/health-science/a-one-time-party-drug-is-helping-people-with-deep- depression/2016/02/01/d3e73862-b490-11e5-a76a-0b5145e8679a_story.html. Accessed June 14, 2016. Reardon S. Nature. 2015;517:130-131. Ketamine: History Ketamine and NMDA Receptor

• Synthesized in 1962 by Calvin Stevens, a Parke-Davis • Dissociative anesthetic chemist seeking an alternative anesthetic to PCP • Uncompetitive high-affinity NMDAR antagonist • FDA approved for use in humans in 1970 • Indications • Binds to PCP “angel dust” site – “…the sole anesthetic agent for diagnostic and surgical within ion channel procedures that do not require skeletal muscle relaxation.” • Membrane depolarization – “…the induction of anesthesia prior to the administration of relieves Mg block, and with co- ” binding, Ca2+ and Na+ other general anesthetic agents. enters cell

– “…to supplement low-potency agents, such as nitrous • 4 NR2 subunits oxide.”

PCP = . Du J, et al. Dialogues Clin Neurosci. US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. 2004;6(2):143-155.

NMDA AGONIST G Ca++ COAGONIST Subanesthetic Dose IV Ketamine RestingReceptorActivated State SITE L GLY SITE Active State U State Rapidly Efficacious in TRD

ALLOSTERIC ALLOSTERIC SITES SITES

Extracellular RestingPotential Space

CHANNEL Depolarized SITE

Mg++

Cytosol Ca++

*P˂ .05; **P ˂ .01; ***P ˂ .001. HAM-D = Hamilton Rating Scale for Depression; SSRI = selective serotonin inhibitor; TRD = treatment-resistant depression. Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966. Zarate CA Jr, et al. Arch Gen Psychiatry. 2006;63(8):856-864.

Rapid Antidepressant Effects of IV Ketamine Percent Improvement from Baseline in MADRS Compared to Psychoactive Control Individual Items 24 Hours after Infusion

Ketamine dose = .5 mg/kg. bReduction in MADRS score 24 hours after infusion was the primary outcome measure and was significantly greater for the ketamine group than for the midazolam group (P ≤ .002). MADRS = Montgomery-Åsberg Depression Rating Scale Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142. Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142. Summary of Acute Response Rates in IV Ketamine – Efficacy in TRD Ketamine Depression Studies At 1 day

At 1 week

Murrough JW, et al. Curr Psychiatry Rep. 2012;14(6):643-649. Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.

Change in Depression Severity after Repeated Ketamine Infusions Eliminates Suicidal Intranasal Ketamine or Placebo Ideation Continuously over a 2-Week Period

* # * #

*P < .001; #P < .05. Lapidus KA, et al. Biol Psychiatry. 2014;76(12):970-976. Price RB, et al. Biol Psychiatry. 2009;66(5):522-526.

Controlled Trial of Ketamine for Repeated Ketamine Infusions in TRD: Suicidal Ideation Pilot Experience 1 24 hr post-infusion 0.5 60.00% 0 50.00% ‐0.5 Baseline 24hrs post‐infusion Ketamine 40.00% ‐1 Midazolam Ketamine 30.00% ‐1.5 Midazolam Group x time: F = 8.8, P = .01 Composite ‐2 1,54 20.00%

Scores (%) Scores Chi-square=4.6, p=.03 ‐2.5 10.00% Standardized Suicide Suicide Standardized ‐3 Patients with All Zero All withPatients 0.00% Reduced scores on 3 combined measures of suicidal cognition 53% of ketamine-treated patients score 0 on all 3 (Beck Suicide Scale, MADRS suicide item, QIDS suicide item) measures

4 Ketamine may work 3.5 best for those at 3 highest risk: 2.5 2 Largest differential effects of 1.5 Ketamine ketamine (over midazolam) 1 Midazolam seen in patients with highest 0.5 suicidality at baseline Item Suicide 0 Change in MADRS in MADRS Change Zero One Two Three Four (Group x baseline SI: β = .55, ‐0.5 QIDS = Quick Inventory of t = 2.5, P = .02) ‐1 Depressive Symptomatology. 1,70 Baseline MADRS Suicide Item Price RB, et al. Depress Anxiety. 2014;31(4):335-343. Murrough JW, et al. Biol Psychiatry. 2013;74(4):250-256. Effects on Positive Caveats Psychotic Symptoms

• Dissociative Side Effects

• General Side Effects

• Effects on Hemodynamics

• Abuse Liability

*4 key BPRS items: conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content. Scores range from 4 to 28. BPRS = Brief Psychiatric Rating Scale. Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.

Pooled Analysis of Behavioral and Dissociative Side Effects Hemodynamic Effects of IV Ketamine in TRD

• Dissociative properties – Things in slow motion – Things seem unreal – Disconnected from body – Sense of body changed

CADSS = Clinician Administered Dissociative States Scale. Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142. Wan LB, et al. J Clin Psychiatry. 2015;76(3):247-252.

Neurocognitive Impact of Ketamine 1 Week following Treatment

Mechanisms of Action: Beyond NMDA Receptors?

Ketamine might work in depression because of activity in non-NMDA receptors

Murrough JW, et al. Neuropsychopharmacology. 2015;40(5):1084-1090. A glutamate pathway to faster acting antidepressants? Effects of Prolonged Stress A single dose of ketamine induced rapid activation of mTOR mediated signaling pathways Prefrontal cortex

Ketamine or NR2B antagonist

AMPA 4E-BP1 ERK, AKT p70S6K mTOR

Increased spine density (24 hr) Synaptic activity inc.

Presynaptic membrane synapsin PSD95 GluR1

Postsynaptic membrane

Duman RS, et al. Science. 2012;338(6103):68-72. mTOR = mammalian target of rapamycin. Cryan JF, et al. Science. 2010;329(5994):913-914.

Signaling Pathways Underlying the Rapid Are the Antidepressant Actions of Ketamine Antidepressant Response to Ketamine Independent of NMDA Receptor Activity?

Duman RS, et al. Trends Neurosci. 2012;35(1):47-56. Zanos P, et al. Nature. 2016;533(7604):481-486. Malinow R. Nature. 2016;533(7604):477-478.

Mechanisms: Suicide Attempts and High Suicidal Intent Associated with Increases in Inflammatory Marker

“Kinder and Gentler” Glutamate-Based Approaches?

Survey of recent developments

KYN pathway induced in suicidal patients, associated with inflammation KYNA = ; KYN = ; QUIN = quinolinic acid; TRP = tryptophan. Schwarcz R, et al. Nat Rev Neurosci. 2012;13(7):465-477. Erhardt S, et al. Neuropsychopharmacology. 2013;38(5):743-752. Candidate Glutamatergic Modulators for Depression Investigational NMDA Receptor Antagonists for Major Depressive Disorder (2016) Na Channel GlyT-1 Inhibitors . . Compound Pharmacology Company Route Status mGluR2 PAMs . Bitopertin . JNJ-40411813 GLYX-13 Glycine site partial Allergan IV Phase 3 . ADX41149 () agonist mGluR2/3 . D- Glycine site partial Antagonists NRX-1074 Allergan oral Phase 2 Glycine Partial agonist . MGS0039 Agonists . LY341495 NR2B-selective . Rapastinel CERC-301 Cerecor Oral Phase 2 mGluR2/3 NAMs . NRX-1074 antagonist . R04491533 Glycine . R04499819 Nonselective, Antagonists noncompetitive Janssen Intranasal Phase 3 . D- Channel blocker mGluR5 NAMs . 4-CI-KYN (AV-101)) . AZD2066 Nonselective . STX-107 uncompetitive EAAT2 NMDAR antagonist Avanir . R04917523 AVP-786 IV Phase 2 . RG7090 Enhancers (deuterated (Otsuka) (Basimglurant) . Ceftriaxone + AMPA quinidine) EAAT = excitatory amino acid Potentiator transporter; NAMs = negative NMDA Complex allosteric modulators; PAMs = AV-101 (4- Glycine site . ORG-26576 VistaGen oral Phase 2 Modulators positive allosteric modulators. Chlorokynurenine) antagonist . 2S,6S-HNK; 2R,6R- Courtesy of Carlos A. HNK Zarate, MD.

Memantine: Lack of Efficacy Early Antidepressant Effect of during Augmentation of Lamotrigine in Bipolar Depression: in Major Depressive Disorder A Double‐Blind, Randomized, Placebo‐Controlled Trial

P = .04. Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966. Anand A, et al. Bipolar Disord. 2012;14(1):64-70.

Riluzole Mechanism of Action Lanicemine in TRD

Increases Inhibits AMPA glutamate trafficking release

Increases Glutamate Regulates reuptake Neurotrophic

Sanacora G, et al. Nat Rev Drug Discov. 2008;7(5):426-437. factors Sanacora G, et al. Mol Psychiatry. 2013;19(9):978-985. Glial Cystine-Glutamate Exchanger and Regulation of Oxidative Stress

NAC Glu D-Cycloserine: Riluzole Enhancement of Extinction Learning

Glu Ketamine GSH Repurposing an old drug used for treatment of tuberculosis

GSH = glutathione; NAC = N-. Gunduz-Bruce H. Brain Res Rev. 2009;60(2):279-286. Gunduz-Bruce 2008

D-Cycloserine D-Cycloserine

• Partial agonist of NMDAR glycine site, with antagonist • Results in anxiety disorders activity at higher doses – DCS works best when fear reduction achieved in- session; it can then truly augment • Preclinical models have found that infusion of DCS in – Dose range 50 mg to 250 mg specific fear extinction circuits aids in the consolidation of extinction learning • Results in substance use disorders • Since 2004, numerous clinical studies (anxiety disorders, – DCS augmentation of cue exposure less compelling, OCD, addictions, , anorexia nervosa), with possibly due to inadequate extinction administration of DCS before exposure/CBT

• Goal: enhance the consolidation of therapeutic learning of CBT

CBT = cognitive-behavioral therapy; DCS = d-cycloserine; OCD = obsessive-compulsive disorder. Otto MW, et al. Biol Psychiatry. 2015;[Epub ahead of print]. Otto MW, et al. Biol Psychiatry. 2015;[Epub ahead of print].

D-Cycloserine (1 g/day) Conclusions Augmentation in TRD

• Response over Time • Glutamate is the main excitatory amino acid neurotransmitter in the CNS • Serum glycine elevations have been associated with SSRI non-response • A major function of its receptors is the modulation of synaptic plasticity, critical for memory, learning, and • Effect size largest in potentially for antidepressant response patients with highest serum glycine levels (≥ 300 μM) • The initial promise of ketamine for depression has • Favorable tolerability sparked interest in the role of specific glutamate receptors • Previous trial of 250 such as NMDA and AMPA mg/day was negative; thus, higher doses might be • Recent evidence supports the role of non-NMDA receptor necessary to induce activity in the cascade of events involved in rapid NMDAR antagonist effect antidepressant activity

Heresco-Levy U, et al. Int J Neuropsychopharmacol. 2013;16(3):501-506. Practical Take-Aways

• While ketamine is increasingly administered off-label in specialized clinics, there is a lack of long-term data to guide clinicians beyond the acute phase

• Given the potential hemodynamic risks of ketamine, monitoring by an ACLS-trained clinician is prudent

• Glutamate modulators such as memantine and riluzole may have limited or no significant benefit for depression

• D-cycloserine (high dose) has promising results for TRD, while a low dose may enhance extinction in fear-based disorders