neurochemical models of schizophrenia: transcending the dopamine dogma leslie citrome, md, mph...

Neurochemical Models of Schizophrenia: Transcending the Dopamine Dogma

Leslie Citrome, MD, MPH

Professor of Psychiatry

New York University School of Medicine

Orangeburg, New York

DisclosureLeslie Citrome, MD, MPH

Leslie Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by the following:

Abbott Laboratories, AstraZeneca Pharmaceuticals,* Avanir Pharmaceuticals, Azur Pharma Inc, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company,* Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals,* Jazz Pharmaceuticals, Merck,* Novartis,* Pfizer Inc,* Sunovion,* Valeant Pharmaceuticals,* and Vanda Pharmaceuticals.

*Denotes a relationship in effect any time during the past 12 months

Maria Mickiewicz

Dislcosure slide left in presentation as it contains additional info besides what is in handout.

Dopamine Pathways and Key Brain Regions

Courtesy of Stahl SM. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

Positive symptoms

Hyperactive!

High

Schizophrenia: Too Much Dopamine?

Mesolimbic pathway


Negative symptoms

Cognitive symptoms

Hypoactive

Affective symptoms

DLPFC

VMPFC

Low

Schizophrenia: Too Little Dopamine?

Mesocortical pathway

Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

Sodhi M, et al. Expert Rev Neurother. 2008;8(9):1389-1406. Copyright © 2011 Expert Reviews .

NONE OF THE CURRENTLY AVAILABLE ANTIPSYCHOTICS

SGAs: D2/5-HT2A Antagonism

ConventionalConventionalfirst generationfirst generation

Atypical Atypical second generationsecond generation

Dopamine D2 antagonist (blocker)

Serotonin 5-HT2A antagonist (blocker)


NEXTNEXT

Dopamine neuron

Dopamine neuron

Serotonin neuron

D2

Atypical antipsychotic

(serotonin-dopamine

antagonist)

5-HT2A Antagonism Stimulates Dopamine Because 5-HT2A Function Is to Act as a Brake on Dopamine “5-HT2A Antagonism Releases the Brake”


NEXTNEXT

“Tuning” Dopamine Output

5-HT2A antagonism

D2 antagonism

DA releasedDA releasedDA blockedDA blocked


Which Action Predominates?

5-HT2A antagonism

D2 antagonism

The answer depends on the region of the brain


Mesocortical Nigrostriatal Tuberoinfundibular

5-HT2A

Treat cognition, mood, negative Sx Minimize EPS Minimize prolactin elevation

Takahashi H, et al. Biol Psychiatry. 2006;59(10):919-928.Courtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

Thus SGAs, Although They Can Block D2 Receptors, Do Not Lead to Decreases in DA in

Regions of the Brain Where DA Is Needed!

Mesolimbic

D2

But SGAs Do Lead to Decreases in DA in Regions of the Brain Where There May Be Too Much!

Treat positive Sx


Limitations of the Dopamine Model

• No consistent dopamine abnormalities have been discovered to date (except perhaps with COMT, an enzyme that breaks up dopamine)

• There are agents that have no D2 binding affinity, yet reduce positive symptoms

• Ketamine induces increases in positive and negative symptoms not blocked by D2 receptor antagonists

Krystal JH, et al. Arch Gen Psychiatry. 1994;51(3):199-214. Patil ST, et al. Nat Med. 2007;13(9):1102-1107.

Schizophrenia: What About Glutamate?• Glutamate is distributed widely and is the primary

excitatory neurotransmitter in the human CNS

• Involved in both fast synaptic transmission and also in plasticity and higher cognitive functions

• Glutamate also can induce neurotoxicity

• Antagonists to glutamate receptors (ketamine and PCP) exacerbate psychotic symptoms and cognitive impairment in patients with schizophrenia AND can induce positive and cognitive symptoms in healthy volunteers

• Susceptibility genes for schizophrenia can influence the function of glutamate receptors

Moghaddam B. Neuron. 2003;40(5):881-884.Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197.

d‑Ser = d-serine

DTNBP1 = dysbindin

mGluR = metabotropic glutamate receptor

NRG1 = neuregulin 1

PSD = post-synaptic density proteins

Sodhi M, et al. Expert Rev Neurother. 2008;8(9):1389-1406. Copyright © 2011 Expert Reviews .

The Glutaminergic Synapse

Glutamate Pathways and Key Brain Regions

thalamus

striatum

brainstem neurotransmitter

centers

NA

NA = nucleus accumbens

Additional deficits in schizophrenia come from

dysfunction outside DLPFC areas, such as auditory

and visual cortex.


Glutamate Receptors: Many Types

• Ionotropic (ie, involve ion channels)

– AMPA: GluR1, GluR2, GluR3, GluR4

– Kainate: GluR5, GluR6, GluR7, GluR KA-1, GluR KA-2

– NMDA: NMDA R1 (isoforms A-G) and NMDA R2 (isoforms A-D)

• Metabotropic (G-protein coupled, ie, involve chemical second messengers)

– Type I (mGluR1 and 5)

– Type II (mGluR2 and 3)

– Type III (mGluR4, 6, 7, and 8)Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197.

Ionotropic Glutamate Receptors: The Fine Print– AMPA (amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)

• Na+ and K+ – rapid kinetics

• Widely distributed, predominantly post-synaptic receptors

• Greatest density of the 3 ionotropic receptors

– Kainate• Na+ and K+ – rapid kinetics

• Predominantly pre-synaptic

• Located in hippocampus and cortex

– NMDA (N-methyl-D-aspartate)• Na+, K+, and Ca+ – slower kinetics

• Structurally complex; activation occurs only if simultaneous glutamate and glycine binding and partial depolarization of the membrane potential

• Predominantly post-synaptic; concentrated primarily in the limbic system, co-localized with AMPA receptors

• Ca+ as a second messenger; wide range intracellular responses → complex neurophysiologic phenomenon

Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197.

Metabotropic Glutamate Receptors: The Fine Print

– Seven transmembrane domains• G-protein coupled• Similar to most dopamine, serotonin, noradrenaline

receptors • Activate phospholipase C or inhibit adenylate cyclase

– Type I—post-synaptic• Occur in hippocampal, amygdala, and thalamic neurons• Less in the cortex and ventral striatum

– Types II and III—presynaptic modulators of glutamate release • Type II mGluR2 restricted to the cortex and dentate gyrus• mGluR3 only metabotropic subtype expressed on glia

Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197.

NMDA, AMPA, and Metabotropic Receptors

Gibb RL. Masters thesis. Lethbridge, Alberta: University of Lethbridge; 2001.Adapted from Hsueh YP, Sheng M. Prog Brain Res. 1998;116:123-131.

Relationships between glutamate receptors and synaptic proteins:

• NMDA, AMPA, and metabotropic (mGluR) receptors bind to specific domain of synaptic proteins, such as PSD-95, GRIP, and HOMER, respectively

• All 3 can be found on a GABA interneuron

• mGluRs are located at the periphery of the synapse, whereas NMDA and AMPA receptors are located more centrally

• mGluRs also can be presynaptic and on glial cells

Metabotropic Glutamate Receptors

• mGluR2 and mGluR3—primarily on presynaptic neurons; coupled to G-proteins

• mGluR3 also is found on glia (astrocytes); regulates the expression of the glial glutamate transporter (ie, reuptake of glutamate)

• Agonists for mGlu2/3 receptors and allosteric potentiators of mGlu2 receptors block the effects of psychomimetics (such as PCP, amphetamine, 5-HT2A agonists) in animals and/or humans

– These agents prevent glutamatergic hyperexcitations in limbic circuits that have been associated with the actions of psychotogens and possibly in the symptoms of schizophrenia

Weinberger DR. Nat Med. 2007;13(9):1018-1019. Copyright © 2007, Nature Publishing Group.Schoepp DD. Neuropsychopharmacology. 2006; 31(Suppl 1):S25-S26.

LY2140023, an mGlu2/3 Agonist: Efficacy and TolerabilityAcute Schizophrenia 28-Day Phase II RCT

• Both LY2140023 and olanzapine resulted in improvements in PANSS, PANSS-P, PANSS-N, CGI-S vs placebo (MMRM, P < 0.0001)

• LY2140023 was not associated with EPS or prolactin elevation; it was associated with nausea

• LY2140023 resulted in weight loss vs placebo compared with weight gain seen with olanzapine

Patil ST, et al. Nat Med. 2007;13(9):1102-1107. Copyright © 2007 Nature Publishing Group.

**P ≤ 0.01; ***P ≤ 0.001

LY2140023

Olanzapine (15 mg/d)

Placebo

15

10

5

0

-5

-10

-15

-20

-25

0 1 2 3 4Week

Ch

ang

e in

PA

NS

S T

ota

l

**

******

******

***

***

**

LY2140023: Current Status

• Second study failed to replicate the first

– This was a failed study where the active control (olanzapine) also did not separate from placebo

• Other studies in progress as noted in www.clinicaltrials.gov (7 listed as of January 30, 2011)

Kinon BJ. Presented at: American Neuropsychiatric Association (ANPA) 21st Annual Meeting; March 17-20, 2010; Tampa, Florida.

Ionotropic Glutamate Receptors as Targets

• AMPA• Ampakine CX516 was tested in a RCT as an adjunct

to antipsychotics—no advantage

• Kainate• Topiramate as an adjunct to antipsychotics—1

positive RCT, 1 equivocal RCT, but topiramate has been associated with cognitive dulling

• NMDA• Multiple RCTs of adjunctive glycine, D-serine, D-cycloserine,

sarcosine, and investigational agents—NMDA receptors may be the best option as a therapeutic target

Goff DC, et al. Neuropsychopharmacology. 2008; 33(3):465-472.Citrome L. Expert Rev Neurother. 2009;9(1):55-71.Kantrowitz JT, Javitt DC. Clin Schizophr Relat Psychoses. 2010;4(3):189-200.

AMPA and Kainate Receptors

Na+

Na+ K+

K+

Na+

Na+ K+

K+

AMPA Kainate

Resting StateCourtesy of Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008.

Na+

Na+ K+

K+

Na+

Na+ K+

K+

AMPA Kainate

Glutamate

Open and Depolarized

Na+Na+

Na+Na+

K+K+

K+K+

Na+ Na+

Na+ Na+ K+

K+

K+K+

AMPA and Kainate Receptors


Na+

Ca++

Glutamate

Resting

Na+

Na+

Ca++Ca++

MgMg++++ Glycine

NMDA

NMDA Receptors


Na+

Na+ Ca++

Ca++

NMDA

Glutamate

Depolarized and Open

Na+Na+

Na+

Na+ Ca++Ca++

Ca++Ca++

GlycineMgMg++++AMPA

or kainate

NMDA Receptors


Cortical glutamate regulates brainstem monoaminergic neurons by:

Glutamatergic fibers projecting to brainstem neurons (accelerator)

Cortical Glutamate Regulates Dopamine Neurons in 2 Possible Ways: Direct Accelerator or Indirect Brake

Direct action as an accelerator

Cortex

+

GLU

DA

Adapted from Tsapakis EM, Travis MJ. Adv Psychiatr Treat. 2002;8(3):189-197.Carlsson A, et al. Br J Psychiatry Suppl. 1999(37):2-6.

Cortical glutamate regulates brainstem monoaminergic neurons by:

Indirectly by fibers projecting to the glutamatergic/gaba-ergic pathway from cortex to brainstem (brake)


Indirect action as brake

Cortex

+-

GLU

GABA

DA


Cortical glutamate regulates brainstem monoaminergic neurons in 2 possible ways:

1. Directly, by means of glutamatergic fibers projecting to brainstem neurons (accelerator)

2. Indirectly by fibers projecting to the glutamatergic/gaba-ergic pathway from cortex to brainstem (brake)

Feedback loops probably exist, possibly via the thalamus and the striatum


Direct action as an accelerator

Indirect action as brake

Cortex

+ +-

GLU GLU

GABA

DA


GABAneuron

DAneuron

gluneuron

OveractivationNormalBaselineHypoactivation

NMDA Receptor Regulation of Mesolimbic Dopamine Pathway: Tonic Inhibition


GABAneuron

DAneuron glu

neuron

High

Positive Symptoms

Normal stateGlutamate acts as a brake on DA

Hypoactive stateGlutamate brake is off

NMDA Receptor Hypofunction in Cortico-Brainstem Projections: Hyperactivity of Mesolimbic Dopamine Pathway



Normal stateCortical glutamate provides tonic excitation of mesocortical DA

glu neuron

NMDA Receptor Regulation of Mesocortical Dopamine Pathways: Tonic Excitation



Low

Affective symptoms

Negative symptoms

Cognitive symptoms

Hypoactive stateExcitation is lost

NMDA Receptor Hypofunction in Cortico-Brainstem Projections: Hypoactivity of Mesocortical Dopamine Pathways

Courtesy of Stahl SM. Stahl's essential psychopharmacology: Neuroscientific basis and practical applications. 3rd ed. Cambridge University Press; 2008. Coyle JT. Cell Mol Neurobiol. 2006;26(4-6):365-384.


More About NMDA Receptors

• In order for the receptor to be activated, both glutamate AND glycine are required, as well as partial depolarization of the membrane potential

• D-serine also has high affinity for the glycine site on NMDA receptors

• An analogue of D-serine, D-cycloserine, also is active at the glycine co-agonist site of NMDA receptors

• Therapeutic options: administer glycine, D-serine, or D-cycloserine or increase the availability of glycine some other way

Stahl SM. CNS Spectr. 2007;12(6):423-427.

Glycine Reuptake Pump Inhibition

• The GLY-T1 reuptake pump is the major route of inactivation of synaptic glycine

• Several GLY-T1 inhibitors exist, including sarcosine and drugs in clinical development

• GLY-T1 inhibitors are analogous to drugs that inhibit reuptake of other neurotransmitters (eg, SSRIs and their actions at the serotonin transporter)

• When GLY-T1 pumps are blocked by a GLY-T1 inhibitor, this increases the synaptic availability of glycine-enhancing NMDA neurotransmission

Stahl SM. CNS Spectr. 2007;12(6):423-427.

Summary

• Although all currently available antipsychotic agents have at least some degree of antagonism at the dopamine D2 receptor, some experimental agents reduce psychotic symptoms in the absence of dopamine D2 receptor antagonism

• Glutamate receptor dysfunction upstream of dopamine can be an explanation for the symptoms of schizophrenia

• Several novel therapeutic targets involving glutamate receptors are under active investigation, including NMDA agonists, glycine transport inhibitors, and metabotropic glutamate receptor agonists

Questions?

[email protected]

neurochemical models of schizophrenia: transcending the dopamine dogma leslie citrome, md, mph...

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