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Copyright © 2011 Neuroscience Education Institute. All rights reserved. Glutamate: The Emerging Frontier of Psychopharmacology for Schizophrenia and Mood Disorders (page 245 in syllabus) Stephen M. Stahl, MD, PhD Adjunct Professor, Department of Psychiatry University of California, San Diego School of Medicine Honorary Visiting Senior Fellow, Cambridge University, UK Sponsored by the Neuroscience Education Institute Additionally sponsored by the American Society for the Advancement of Pharmacotherapy This activity is supported by an educational grant from Sunovion Pharmaceuticals Inc.

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Page 1: Glutamate: The Emerging Frontier of Psychopharmacology for ...cdn.neiglobal.com/content/congress/2011/encore_glutamate.pdf · Glutamate: The Emerging Frontier of Psychopharmacology

Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Glutamate: The Emerging Frontier

of Psychopharmacology for

Schizophrenia and Mood Disorders

(page 245 in syllabus)

Stephen M. Stahl, MD, PhD

Adjunct Professor, Department of Psychiatry

University of California, San Diego School of Medicine

Honorary Visiting Senior Fellow, Cambridge University, UK

Sponsored by the Neuroscience Education Institute

Additionally sponsored by the American Society for the Advancement of Pharmacotherapy

This activity is supported by an educational grant from Sunovion Pharmaceuticals Inc.

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Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Faculty Author / Presenter

Stephen M. Stahl, MD, PhD, is an adjunct professor in the department of psychiatry at

the University of California, San Diego School of Medicine, and an honorary visiting

senior fellow at the University of Cambridge in the UK.

Grant/Research: AstraZeneca, BioMarin, Dainippon Sumitomo, Dey, Forest, Genomind,

Lilly, Merck, Pamlab, Pfizer, PGxHealth/Trovis, Schering-Plough, Sepracor/Sunovion,

Servier, Shire, Torrent

Consultant/Advisor: Advent, Alkermes, Arena, AstraZeneca, AVANIR, BioMarin, Biovail,

Boehringer Ingelheim, Bristol-Myers Squibb, CeNeRx, Cypress, Dainippon Sumitomo,

Dey, Forest, Genomind, Janssen, Jazz, Labopharm, Lilly, Lundbeck, Merck,

Neuronetics, Novartis, Ono, Orexigen, Otsuka, Pamlab, Pfizer, PGxHealth/Trovis,

Rexahn, Roche, Royalty, Schering-Plough, Servier, Shire, Solvay/Abbott,

Sunovion/Sepracor, Valeant, VIVUS,

Speakers Bureau: Dainippon Sumitomo, Forest, Lilly, Merck, Pamlab, Pfizer,

Sepracor/Sunovion, Servier, Wyeth

Individual Disclosure Statement

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Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Objectives

• To discuss the pathophysiology of schizophrenia

and mood disorders in relation to glutamate

• To show how glutamate pharmacology is linked

to new drug development

• To identify relevant compounds in the pipeline

and discuss their novel mechanisms of action

and potential clinical utility in schizophrenia and

mood disorders

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Copyright © 2011 Neuroscience Education Institute. All rights reserved.

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Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Glutamate Pharmacology

• Glutamate receptors

• Glutamate synthesis and metabolism

• Role of cotransmitters glycine and d-serine

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Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Background: Glutamate and Glycine

Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. 2008.

Glutamate and glycine are amino acids.

They are used:

• For protein synthesis

• As neurotransmitters and cotransmitters

Glutamate works as a

neurotransmitter at 2 types

of glutamate receptors:

1. Ionotropic: Those linked to ion

channels (including NMDA and

AMPA)

2. Metabotropic: Those linked to

second messenger systems

Glycine works as:

1. A neurotransmitter at glycine

synapses

2. A co-transmitter at the

glutamate receptor NMDA

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Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Background:

Glutamate AMPA and NMDA Receptors

Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. 2008.

AMPA and NMDA are ionotropic glutamate receptors

AMPA

1. Activated when bound by

glutamate

2. Activation opens its ion

channel

3. This results in neuronal

depolarization

NMDA

Requires 3 steps to be activated and

to open its ion channel:

1. Neuronal depolarization

(AMPA activation) to release its

magnesium plug

2. Glutamate binding

3. Glycine binding

This results in long-term potentiation,

which is linked to regulation of

learning, memory, and dopamine

neurotransmission.

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Glutamate Receptors

EAAT

EAAT = Excitatory amino acid transporter

vGlu-T = Vesicular glutamate transporter

NMDA = N-methyl-d-aspartate

Postsynaptic metabotropic

receptor

EAAT

Presynaptic metabotropic

receptor

vGlu-T

Kainate receptor

AMPA receptor NMDA

receptor

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Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Glutamate Receptors

Postsynaptic metabotropic

receptor Kainate receptor

AMPA receptor NMDA

receptor

vGlu-T

EAAT

Presynaptic metabotropic

receptor

EAAT = Excitatory amino acid transporter

vGlu-T = Vesicular glutamate transporter

NMDA = N-methyl-d-aspartate

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Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Glutamate Receptors

Postsynaptic metabotropic

receptor Kainate receptor

AMPA receptor NMDA

receptor

vGlu-T

EAAT

Presynaptic metabotropic

receptor

EAAT = Excitatory amino acid transporter

vGlu-T = Vesicular glutamate transporter

NMDA = N-methyl-d-aspartate

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Glutamate Receptors

Postsynaptic metabotropic

receptor Kainate receptor

AMPA receptor NMDA

receptor

vGlu-T

EAAT

Presynaptic metabotropic

receptor

EAAT = Excitatory amino acid transporter

vGlu-T = Vesicular glutamate transporter

NMDA = N-methyl-d-aspartate

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Stahl. Stahl’s essential psychopharmacology.

3rd ed. 2008.

NMDA Receptors:

Coincidence Detectors

AMPA receptor NMDA receptor

Mg++

glycine

glutamate

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activated

Stahl. Stahl’s essential psychopharmacology.

3rd ed. 2008.

NMDA Receptors:

Coincidence Detectors

AMPA receptor NMDA receptor

Mg++

glycine

glutamate

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Copyright © 2011 Neuroscience Education Institute. All rights reserved.

Na+ Ca++

activated activated

Stahl. Stahl’s essential psychopharmacology.

3rd ed. 2008.

Long-term

potentiation

NMDA Receptors:

Coincidence Detectors

AMPA receptor NMDA receptor

glycine

Mg++ glutamate

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Glutamate Is Recycled and Regenerated

EAAT

Glutamate

Glutamine

synthetase

Glutamine

Reversed

SNAT

SNAT

Glial cell

Glutaminase

Glutamate

vGly-T

vGly-T = Vesicular glycine

transporter

SNAT = Specific neutral

amino acid transporter

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Glycine

neuron

Glutamate

neuron

Reversed

GLY-T1

(release)

GLY-T1

(reuptake)

Glial cell

L-SER-T

GLY-T

2

Glycine

L-serine

SHMT

Glutamate and Glycine: Cotransmitters at NMDA Receptors

NMDA currents enhanced

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Glutamate and Schizophrenia

• NMDA hypofunction hypothesis of

schizophrenia

• Neurodevelopmentally abnormal glutamate

synapses

• Hypofunctional NMDA receptors

• Overstimulation of downstream glutamate

receptors

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Cortical Glutamate Regulation: Normal

GABA inter-

neuron Glutamate

neuron

Glutamate neuron

NMDA GABA

glu

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Cortical Glutamate Regulation: Normal

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Ketamine blockade of

NMDA receptors

PCP-Ketamine: Model of Schizophrenia

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Ketamine blockade of

NMDA receptors

PCP-Ketamine: Model of Schizophrenia

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Glutamate and the Dopamine Hypothesis of

Schizophrenia

• So how does all of this relate to the dopamine

hypothesis of schizophrenia?

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Overactivation Normal Baseline Hypoactivation

Mesolimbic Dopamine Pathway

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Positive

symptoms

HIGH

Mesolimbic Dopamine Pathway

Overactivation Normal Baseline Hypoactivation

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Mesocortical Dopamine Pathway

Overactivation Normal Baseline Hypoactivation

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Mesocortical Dopamine Pathway

Negative symptoms

LOW

Cognitive symptoms

Overactivation Normal Baseline Hypoactivation

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Copyright © 2011 Neuroscience Education Institute. All rights reserved. Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. 2008; Woo TW et al. Brain Res 2008.

NMDA Glutamate Hypoactivity Leads to

Mesolimbic Dopamine Hyperactivity and

Positive Symptoms of Schizophrenia

Positive

symptoms

Overactivation Normal Baseline Hypoactivation

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Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. 2008; Woo TW et al. Brain Res 2008.

Negative

symptoms

NMDA Glutamate Hypoactivity Leads to

Mesolimbic Dopamine Hypoactivity and

Negative Symptoms of Schizophrenia

Overactivation Normal Baseline Hypoactivation

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10-123

Novel Glutamatergic Treatments for Schizophrenia: Direct Acting Glycine Site Agonists

Glutamate

neuron

Glutamate

Direct acting glycine

site agonists

NMDA currents enhanced

d-cycloserine

d-serine

Glycine

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Novel Glutamatergic Treatments for Schizophrenia:

Glycine Transporter 1 Inhibitors (e.g., bitropertin RGH1678)

Glutamate

neuron

Glutamate

NMDA currents not enhanced

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Novel Glutamatergic Treatments for Schizophrenia:

Glycine Transporter 1 Inhibitors (e.g., bitropertin RGH1678)

Glutamate

neuron

Glycine GlyT1

inhibitor Glutamate

NMDA currents enhanced

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Copyright © 2011 Neuroscience Education Institute. All rights reserved. Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. 2008; Woo TW et al. Brain Res 2008.

Positive

symptoms

Restored

NMDA

receptor

function

Novel Glutamatergic Treatments for Positive

Symptoms of Schizophrenia: Glycine Transporter 1 Inhibitors

(e.g., bitropertin RGH1678)

Overactivation Normal Baseline Hypoactivation

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Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. 2008; Woo TW et al. Brain Res 2008.

Negative

symptoms

Increased

NMDA

receptor

activation

Novel Glutamatergic Treatments for Negative

Symptoms of Schizophrenia: Glycine Transporter 1 Inhibitors

(e.g., bitropertin RGH1678)

Overactivation Normal Baseline Hypoactivation

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Glutamate and New Drugs for Schizophrenia

• Reduce overstimulation of downstream

glutamate receptors

– mGluR 2/3 presynaptic agonists

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Ketamine blockade of

NMDA receptors

PCP-Ketamine Model of Schizophrenia

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9-37a

mGluR type II/III

presynaptic

autoreceptor

Presynaptic mGluR 2/3:

Autoreceptor Regulating Glutamate Release

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9-37b

mGluR type II/III

presynaptic

autoreceptor

Presynaptic mGluR 2/3:

Autoreceptor Regulating Glutamate Release

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Cortical Glutamate Regulation: mGluR 2,3 Agonist LY2140023

Reverses Symptoms of Schizophrenia

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mGluR2/3 Agonist: Phase II Clinical Trial

Patil et al. Nat Med

2007;13(9):1102-7.

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• mGluR2/3 presynaptic agonist LY2140023

• Positive proof of concept in schizophrenia

• Second study failed

• Seizures 3/600

• Third monotherapy trial in progress

• Add-on trial in progress

Glutamate and Schizophrenia: Compensate for Downstream Glutamate Release Secondary to

Hypofunctional NMDA Systems?

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Glutamate, Mood Disorders,

and New Drug Treatments

• Possible glutamate excess in depression

• Unipolar, treatment resistant, bipolar, and suicidal

• MRS scans

• CSF studies

• Improvement by anti-glutamate treatments

• Opposite pharmacology from schizophrenia?

• Lamotrigine/riluzole

• Memantine/amantadine

• Ketamine

• NR2B selective antagonists

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Possible Sites of Action of Lamotrigine and Riluzole on Glutamate Release

Glutamate

neuron

Lamotrigine

Riluzole Riluzole Lamotrigine

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Ketamine

• NMDA blocker

• Like phencyclidine, induces schizophrenia-like

symptoms in normal volunteers and exacerbates

them in patients

• Short-term, low-dose IV ketamine does not

induce full range of psychotic symptoms in

experimental setting

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Site of Action of Ketamine: Binds to Open

Channel at PCP Site to Block NMDA Receptor

PCP site

(in the ion

channel)

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Site of Action of Ketamine: Binds to Open

Channel at PCP Site to Block NMDA Receptor

Ketamine

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Ketamine blockade of

NMDA receptors

PCP-Ketamine: Model of Schizophrenia or

Novel Antidepressant?

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Ketamine blockade of

NMDA receptors

PCP-Ketamine: Model of Schizophrenia or

Novel Antidepressant?

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New Approaches to Resistant Depression

Published online 7 August 2006 | Nature | doi:10.1038/news060807-1

Club drug finds use as antidepressant

• Psychedelic ketamine hits the blues surprisingly fast

• Pills popped in a nightclub are potential therapeutics

too

• The "club drug" ketamine may be the fastest-acting

antidepressant ever tested, researchers report today

• A team based at the U.S. National Institute of Mental

Health in Bethesda, Maryland, studied ketamine in

17 people with major depression. All the subjects

had failed to respond to treatment with standard

antidepressant drugs or more drastic methods, such

as electroshock therapy. But 71% felt better the day

after taking ketamine, and 35% still felt better a week

later. None improved when dosed with a placebo

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Antidepressant Effect of Ketamine Within Hours

in Patients With Treatment-Resistant Depression

HDRS: Hamilton Depression Rating Scale

Zarate CA Jr et al. Arch Gen Psychiatry 2006;63:856-64.

21

-Ite

m H

DR

S S

core

15

25

0

5

10

30

20

-60 min

40 min

90 min

110 min

230 min

Day 1

Day 2

Day 3

Day 7

Ketamine

*

*

† ‡

‡ ‡

Placebo

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The bottom slide shows regeneration of synaptic connections

in group receiving ketamine compared to control group

(Courtesy of Yale University)

Ketamine Rapidly Increases the Density and Function of the Dendritic Spines of Layer V Pyramidal Neurons in the Prefrontal Cortex

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Fast Action of Ketamine

AMPA, {alpha}-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate;

4E-BP1, eukaryotic initiation factor 4E binding protein 1; ERK,

extracellular signal-regulated kinase; GluR1, AMPA receptor subunit

1; mTOR, mammalian target of rapamycin; NMDA, N-methyl-D-

aspartate; p70S6K, p70S6 kinase.

Forced Swim Test

• Behavioral paradigm in which rats or mice are forced to swim in an environment from which there is no escape (a narrow water-filled cylinder). After an initial period of vigorous activity, during which the rodent attempts to escape, there is a period of relative immobility, with the subject making only minimal efforts to stay afloat

• Acute antidepressant treatment reduces the time spent immobile

• The forced swim test is highly predictive of antidepressant activity. It is generally considered the gold standard for screening of putative antidepressants

In rats, a single dose of ketamine activates

the mTOR pathway in the prefrontal cortex,

increasing the expression of synaptic

proteins and the density of dendritic spines

and inducing an antidepressant response

within a day

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=

The NMDA Receptor Has Subtypes Including

NR2A and NR2B

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• Taxoprodil – CP101,606 – Positive proof of concept – Pfizer

• AstraZeneca compound – In Phase II

• EVT101/103 – In Phase II – Evotec/Roche

• Radiprodil – RGH 896 – Gedeon Richter – Phase II

• MK 0657 – Merck/NIMH – Phase II

NR2B Selective NMDA Antagonists

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• Why would a mechanism associated with a human model of schizophrenia cause improvement in depression?

• "Rebooting" the system?

• One dose? Sustaining the effect over time?

• Treatment-resistant depression?

• Consequence of downstream actions: Although this blocks glutamate at one receptor, the release of glutamate results in stimulation of all the other glutamate receptor subtypes

• Which is the desired action?

NR2B Selective NMDA Antagonists:

Some Key Questions

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Summary

• The pathophysiology of schizophrenia and mood

disorders is linked to glutamate

• New drugs for schizophrenia target

hypothetically hypoactive NMDA receptor

functioning

• New drugs for mood disorders target

hypothetically overactive glutamate functioning