Glutamate and Psychiatry: Where Are We, and What Does the Future Hold?

Sanjay J. Mathew, MDProfessor of Psychiatry and Behavioral SciencesJohnson Family Chair for Research in PsychiatryMenninger Department of Psychiatry and Behavioral SciencesBaylor College of MedicineStaff Physician, Michael E. Debakey VA Medical CenterHouston, Texas

Glutamate, NMDA Receptors, and the Quest for Rapid Antidepressants

The story of ketamine

Clomipramine

(EU 1960, US 1989)

Trazodone (1981)

Evolution of Antidepressants: 1950–1980s

Imipramine (1957)

1950 1960

1970 1980

Nortriptyline (1977)

Isocarboxazid (1959) Amitriptyline (1961)

Phenelzine (1961)

Desipramine (1964)

Protriptyline (1967)

Tranylcypromine (1969)

Doxepin (1969)

Trimipramine (1979)

Bupropion (1985)

Fluoxetine (1987)

Maprotiline (1987)

Amoxapine (1989)

1955 1965

1975 1985

Antidepressants 1990s–2015

Sertraline (1991)

1990 2000

2010

Paroxetine (1992)

Venlafaxine (1993)

Mirtazapine (1996)

Milnacipran (EU – 1996)

Nefazodone (1994)

Fluvoxamine (OCD – 1994)

Citalopram (1998)

Escitalopram (2002)

Duloxetine (2004)

Desvenlafaxine

(2008)Selegiline patch (2005)Vilazodone (2011)

Levomilnacipran (2013)

Vortioxetine(2013)

Brexpiprazole (2015)

Fluoxetine /

Olanzapine (2003)

L-methylfolate (2006)

1995

Quetiapine XR

(MDD – 2009)

2000 2005

Aripiprazole(MDD – 2007)

2015

Nu

mb

er o

f M

ech

anis

tica

lly

Dis

tin

ct D

rug

s

Slow Progress in Discovering Novel Drug Targets Beyond Serotonin, Norepinephrine, and Dopamine

Insel TR, et al. Mol Psychiatry. 2006;11(1):11-17.

What are Key Unmet Needsfor Antidepressants?

• Rapid onset of activity

• Prevention of relapse

• Impacts suicide risk

• Low side effect burden

• Addresses underlying pathophysiology

Glutamate

CNS = central nervous system; TCA = tricarboxylic acid.Mason G. Presented at: 71st Annual Meeting of the Society of Biological Psychiatry; May 12-14, 2016: Atlanta, GA.

• Most common excitatory amino acid neurotransmitter in CNS

• Fundamental to brain bioenergetics and metabolism

• Derived from both neuronal/glial pathways as well as TCA cycle

• Distribution of glutamate in compartments

– Neurons: 90%–95%

– Glia: 5%–10%

– Blood: 0.02%

– Extracellular space: 0.0008% (1/100,000 of total)

Tight Physiological Control of Glutamatergic Neurotransmission and Potential Therapeutic Targets

mGluR = metabotropic glutamate receptor; NMDA = N-methyl-D-aspartate.Sanacora G, et al. Nat Rev Drug Discov. 2008;7(5):426-437. Sanacora G, et al. 2008

+TCA Cycle

Extrasynaptic Glu

Extrasynaptic NMDA

Voltage dependent

Group I mGluR

Group II

Enhancement of Cellular Plasticity May Be Final Common Pathway for Antidepressant Treatments

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.Mathew SJ, et al. Neuropsychopharmacology. 2008;33(9):2080-2092.

5-HT1A

Attenuation

NMDA Antagonists Show Antidepressant-Like Activity in Preclinical Models

AD = antidepressant; LTP = long-term potentiation.Skolnick P, et al. Trends Pharmacol Sci. 2009;30(11):563-569.

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

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

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

The Washington Post

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.

Onetime party drug hailed as miracle for treating severe depressionBy Sara Solovitch February 1, 2016

Rave drug tested against depression: Companies and clinicians turn to ketamine to treat mental-health

disorder as pipeline of new drugs dries up

Reardon S. Nature. 2015;517:130-131.

Ketamine: History

PCP = phencyclidine.US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

• Synthesized in 1962 by Calvin Stevens, a Parke-Davis chemist seeking an alternative anesthetic to PCP

• FDA approved for use in humans in 1970 • Indications

– “…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.”

• Dissociative anesthetic

• Uncompetitive high-affinity NMDAR antagonist

• Binds to PCP “angel dust” site within ion channel

• Membrane depolarization relieves Mg block, and with co-agonist binding, Ca2+ and Na+ enters cell

• 4 NR2 subunits

Ketamine and NMDA Receptor

Du J, et al. Dialogues Clin Neurosci. 2004;6(2):143-155.

Extracellular Space

Cytosol

AGONIST SITE

COAGONIST SITE

CHANNEL SITE

Restin

g P

oten

tialALLOSTERIC

SITESALLOSTERIC

SITES

Ca++

GLU

GLY

NMDAReceptorResting StateActivated

State

Depolarized

Active StateCa++

Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.

Mg++

Subanesthetic Dose IV Ketamine Rapidly Efficacious in TRD

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

Rapid Antidepressant Effects of IV Ketamine Compared to Psychoactive Control

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.

Percent Improvement from Baseline in MADRS Individual Items 24 Hours after Infusion

Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.

Summary of Acute Response Rates in Ketamine Depression Studies

Murrough JW, et al. Curr Psychiatry Rep. 2012;14(6):643-649.

IV Ketamine – Efficacy in TRD

Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.

At 1 day

At 1 week

Change in Depression Severity after Intranasal Ketamine or Placebo

* *# #

*P < .001; #P < .05.Lapidus KA, et al. Biol Psychiatry. 2014;76(12):970-976.

Repeated Ketamine Infusions Eliminates Suicidal Ideation Continuously over a 2-Week Period

Price RB, et al. Biol Psychiatry. 2009;66(5):522-526.

‐3

‐2.5

‐2

‐1.5

‐1

‐0.5

0

0.5

1

Baseline 24hrs post‐infusion

Sta

nd

ard

ized

Su

icid

e C

om

po

sit

e

Ketamine

Midazolam

Reduced scores on 3 combined measures of suicidal cognition (Beck Suicide Scale, MADRS suicide item, QIDS suicide item)

53% of ketamine-treated patients score 0 on all 3 measures

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

Pat

ien

ts w

ith

All

Zer

o

Sco

res

(%)

24 hr post-infusion

Ketamine

MidazolamGroup x time: F

1,54 = 8.8, P = .01

Chi-square=4.6, p=.03

‐1

‐0.5

0

0.5

1

1.5

2

2.5

3

3.5

4

Zero One Two Three Four

Ch

ang

e in

MA

DR

S

Su

icid

e It

em

Baseline MADRS Suicide Item

Ketamine

Midazolam

Ketamine may work best for those at highest risk:

Largest differential effects of ketamine (over midazolam) seen in patients with highest suicidality at baseline

(Group x baseline SI: β = .55, t1,70

= 2.5, P = .02)QIDS = Quick Inventory of

Depressive Symptomatology. Price RB, et al. Depress

Anxiety. 2014;31(4):335-343.

Controlled Trial of Ketamine for Suicidal Ideation

Repeated Ketamine Infusions in TRD: Pilot Experience

Murrough JW, et al. Biol Psychiatry. 2013;74(4):250-256.

Caveats

• Dissociative Side Effects

• General Side Effects

• Effects on Hemodynamics

• Abuse Liability

Effects on Positive Psychotic Symptoms

*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.

Dissociative Side Effects

CADSS = Clinician Administered Dissociative States Scale.Murrough JW, et al. Am J Psychiatry. 2013;170(10):1134-1142.

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

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

Wan LB, et al. J Clin Psychiatry. 2015;76(3):247-252.

Neurocognitive Impact of Ketamine 1 Week following Treatment

Murrough JW, et al. Neuropsychopharmacology. 2015;40(5):1084-1090.

Mechanisms of Action: Beyond NMDA Receptors?

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

Effects of Prolonged Stress

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.

Increased spine density (24 hr)

Presynaptic membrane

Ketamine or NR2B antagonist

ERK, AKT

mTOR

synapsin

Postsynaptic membrane

PSD95 GluR1

Synaptic activity inc.

4E-BP1 p70S6K

AMPA

Prefrontal cortex

A glutamate pathway to faster acting antidepressants? A single dose of ketamine induced rapid activation of

mTOR mediated signaling pathways

Duman RS, et al. Trends Neurosci. 2012;35(1):47-56.

Signaling Pathways Underlying the Rapid Antidepressant Response to Ketamine

Are the Antidepressant Actions of Ketamine Independent of NMDA Receptor Activity?

Zanos P, et al. Nature. 2016;533(7604):481-486. Malinow R. Nature. 2016;533(7604):477-478.

KYN pathway induced in suicidal patients, associated with inflammation

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

Inflammatory Marker Quinolinic Acid

KYNA = kynurenic acid; KYN = kynurenine; 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.

“Kinder and Gentler” Glutamate-Based Approaches?

Survey of recent developments

NMDA Complex Modulators

Na Channel Riluzole

mGluR2 PAMs JNJ-40411813 ADX41149

mGluR2/3 Antagonists MGS0039 LY341495

mGluR2/3 NAMs R04491533 R04499819

mGluR5 NAMs AZD2066 STX-107 R04917523 RG7090

(Basimglurant)

GlyT-1 Inhibitors Sarcosine Bitopertin

Glycine Agonists D-serine

Glycine Partial Agonists Rapastinel NRX-1074

Glycine Antagonists D-cycloserine 4-CI-KYN (AV-101))

EAAT2 Enhancers Ceftriaxone

AMPA Potentiator ORG-26576 2S,6S-HNK; 2R,6R-

HNK

EAAT = excitatory amino acid transporter; NAMs = negative

allosteric modulators; PAMs = positive allosteric modulators.

Courtesy of Carlos A. Zarate, MD.

Candidate Glutamatergic Modulators for Depression Investigational NMDA Receptor Antagonists for Major Depressive Disorder (2016)

Compound Pharmacology Company Route Status

GLYX-13 (rapastinel)

Glycine site partial agonist

Allergan IV Phase 3

NRX-1074Glycine site partial

agonistAllergan oral Phase 2

CERC-301NR2B-selective

antagonist Cerecor Oral Phase 2

EsketamineNonselective,

noncompetitive Channel blocker

Janssen Intranasal Phase 3

AVP-786

Nonselective uncompetitive

NMDAR antagonist(deuterated

dextromethorphan + quinidine)

Avanir(Otsuka)

IV Phase 2

AV-101 (4-Chlorokynurenine)

Glycine site antagonist

VistaGen oral Phase 2

Memantine: Lack of Efficacy in Major Depressive Disorder

Newport DJ, et al. Am J Psychiatry. 2015;172(10):950-966.

Early Antidepressant Effect of Memantine during Augmentation of Lamotrigine in Bipolar Depression:

A Double‐Blind, Randomized, Placebo‐Controlled Trial

P = .04.Anand A, et al. Bipolar Disord. 2012;14(1):64-70.

Inhibitsglutamate

release

IncreasesGlutamate reuptake

Riluzole Mechanism of Action

Sanacora G, et al. Nat Rev Drug Discov. 2008;7(5):426-437.

IncreasesAMPA

trafficking

RegulatesNeurotrophic

factors

Lanicemine in TRD

Sanacora G, et al. Mol Psychiatry. 2013;19(9):978-985.

Glial Cystine-Glutamate Exchanger and Regulation of Oxidative Stress

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

NAC

GSH

Glu

GlutathioneKetamine

Riluzole

Glu

D-Cycloserine: Enhancement of Extinction Learning

Repurposing an old drug used for treatment of tuberculosis

D-Cycloserine

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

• Partial agonist of NMDAR glycine site, with antagonist activity at higher doses

• Preclinical models have found that infusion of DCS in specific fear extinction circuits aids in the consolidation of extinction learning

• Since 2004, numerous clinical studies (anxiety disorders, OCD, addictions, schizophrenia, anorexia nervosa), with administration of DCS before exposure/CBT

• Goal: enhance the consolidation of therapeutic learning of CBT

D-Cycloserine

Otto MW, et al. Biol Psychiatry. 2015;[Epub ahead of print].

• Results in anxiety disorders – DCS works best when fear reduction achieved in-

session; it can then truly augment– Dose range 50 mg to 250 mg

• Results in substance use disorders– DCS augmentation of cue exposure less compelling,

possibly due to inadequate extinction

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

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

• Response over Time• Serum glycine elevations

have been associated with SSRI non-response

• Effect size largest in patients with highest serum glycine levels (≥ 300 μM)

• Favorable tolerability

• Previous trial of 250 mg/day was negative; thus, higher doses might be necessary to induce NMDAR antagonist effect

Conclusions

• Glutamate is the main excitatory amino acid neurotransmitter in the CNS

• A major function of its receptors is the modulation of synaptic plasticity, critical for memory, learning, and potentially for antidepressant response

• The initial promise of ketamine for depression has sparked interest in the role of specific glutamate receptors such as NMDA and AMPA

• Recent evidence supports the role of non-NMDA receptor activity in the cascade of events involved in rapid antidepressant activity

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 riluzolemay 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