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The Glutamate Hypothesis and the Glutamate Linked

Treatments of

Schizophrenia

Dr Mohamed AbdelghaniAss. Lecturer Of PsychiatryZagazig Faculty Of Medicine

Available at: http://www.slideshare.net/mabdelghani 04/12/2023

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Contents (I) The Glutamate System(II) Glutamate System and

Schizophrenia

a- NMDA Receptors Hypofunction Theory

The Glutamate theory vs. the Dopamine theory

in schizophrenia

b- The Glutamate & Neurodevelopmental

Theory

c- The Glutamate & Neurodedegenarative

Theory

(III) Glutamate Linked Treatments of Schizophrenia

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(I) The Glutamate SystemL-Glutamate: “the king of neurotransmission”

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The Glutamate System: (Moghaddam, 2005)

Glutamate is the major excitatory

neurotransmitter in CNS (the king of

neurotransmission).

Nearly 50% of the neurons in the

brain, esp. projecting from the

cerebral cortex, use glutamate as

their neurotransmitter.04/12/2023

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Possible therapeutic applications

(MRC Centre for Synaptic Plasticity 2010)

Multifacet ischemia

Epilepsy Parkinson's

disease Alzheimer’s

disease Hyperalgesia

Diabetes Multiple SclerosisSchizophrenia Anxiety Depression Others

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Glutamate Receptors: (MRC Centre for Synaptic Plasticity 2010)

Glutamate acts via two classes of receptors “in both neurones and glial cells”:

Ligand gated ion channels (Ionotropic

receptors):

Four groups (AMPA, NMDA, Kinate and

Delta receptors).

G-protein coupled (Metabotropic

receptors).

They are further broken down into three

groups and eight subgroups: (mGlu1-mGlu8).

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Metabotropic Glutamate Receptors

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(II) Glutamate system and schizophrenia

(1) NMDA Receptors Hypofunction Hypothesis of Schizophrenia

• The Glutamate theory vs. the Dopamine theory in schizophrenia

(2) The Glutamate Excitotoxicity as part of the Neurodevelopmental Theory of Schizophrenia

• The excessive pruning theory

(3) The Glutamate Excitotoxicity as part of the Neurodedegenarative Model of Schizophrenia

• The excessive apoptosis theory

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(1) NMDA Receptors Hypofunction Hypothesis of Schizophrenia:The Glutamate theory vs. the

Dopamine theory in schizophrenia

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Glutamate system and schizophrenia

The idea of a glutamatergic

abnormality in schizophrenia was first

proposed by Kim and colleagues in

1980 (Kim et al., 1980) based on their

findings of low cerebrospinal fluid

(CSF) glutamate levels in patients with

schizophrenia.

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Glutamate system and schizophrenia

Studies about Antiglutamatergic substances:

Phencyclidine (PCP) or ketamine

produces "schizophrenia-like"

symptoms in healthy individuals and

exacerbates pre-existing symptoms in

patients with schizophrenia (Javitt

et al., 1991; Krystal et al., 1994;

Lahti et al., 1995).

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Glutamate system and schizophrenia

Genetic studies: Most of genes that have recently been

associated with an increased risk for schizophrenia can influence functions linked to glutamate receptors (Harrison et al., 2003; Moghaddam, 2003).

Postmortem receptors studies: Studies show changes in glutamate

receptor binding, transcription, and subunit protein expression in the prefrontal cortex, thalamus, and hippocampus of subjects with schizophrenia (Clinton and Meador-Woodruff, 2004).

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Glutamate system and schizophrenia

Postmortem enzymes studies: Levels of amino acids N-acethylaspartate

(NAA) and N-acethylaspartylglutamate (NAAG), and the activity of the enzyme that cleaves NAAG to NAA and glutamate are altered in the CSF and postmortem tissue from individuals with schizophrenia (Tsai et al., 1995).

Brain imaging studies: SPECT studies using a tracer for the

NMDA receptor have reported reduced NMDA receptor binding in the hippocampus of medication-free patients (Pilowsky et al., 2005).

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The Glutamate theory vs.

the Dopamine theory in

schizophrenia

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Key DA Pathways

(a) The nigrostriatal pathway. (b) The mesolimbic pathway. (c) The mesocortical pathway (dorsolateral prefrontal cortex & ventromedial cortex). (d) The tuberoinfundibular pathway. (e) The thalamic DA pathway

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The DA Hypothesis of Schizophrenia: Positive Symptoms

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Dopamine Theory: the golden triad

1. Drugs that increase dopamine, such as amphetamine and cocaine, can cause psychosis.

2. Antidopaminergic drugs can  improve psychosis.

3. Mechanism : overactivity in the mesolimbic dopamine pathway could be the mediator of positive symptoms of schizophrenia such as delusions and hallucinations.

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The DA Hypothesis of Schizophrenia: Negative, Cognitive, and Affective Symptoms

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Dopamine Theory: Problems

It explains only part of schizophrenia (positive symptoms not negative symptoms).

Anti-dopamenergic drugs usually: make negative symptoms worse in

patients. induce negative symptoms in healthy

people. Atypical antipsychotic drugs e.g.

Clozapine (with weaker anti-dopaminergic activity) are better anti-schizophrenic drugs.

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Dopamine Theory: problems cont.

Under activity in  the meso-cortical dopamine pathway is hypothesized to be the mediator of negative symptoms of schizophrenia: This indicates that reduced dopamine

activity is the problem rather than dopamine overactivity.

DA theory is a “psychosis theory” more than it is a “schizophrenia theory”.

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Role of Glutamate in the Mesocortical System

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Role of Glutamate in the Mesolimbic System

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(2) The Glutamate Excitotoxicity as part of the Neurodevelopmental Theory

of Schizophrenia

The excessive pruning theory

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Neurodevelopmental Theory of Schizophrenia (Fatemi & Folsom, 2009)

Schizophrenia could be the result of an early brain insult, which affects brain development leading to abnormalities in the mature brain (Murray et al, 1992).

The theory has been postulated since Kraeplin in the early 20th century.

The cause of the brain lesion could be either:

Abnormal genes, which impair brain development.

Some foetal or neonatal adversity. 04/12/2023

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Neurodevelopmental Theory of Schizophrenia: Evidence (Fatemi &

Folsom, 2009) Congenital Abnormalities: e.g. agenesis of

corpus callosum, stenosis of sylvian aqueduct, cerebral hamartomas, low-set ears, epicanthal eye folds, etc.

Environmental Factors: e.g. obstetric and perinatal complications, periventicular hemorrhages, hypoxia, and ischemic injuries and prenatal viral infections.

Biological markers: e.g. changes in the proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis.

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Neurodevelopmental Theory of Schizophrenia: Evidence (Fatemi &

Folsom, 2009)

Genetics studies: e.g. various genes, involved in schizophrenia, were also involved in signal transduction, cell growth and migration, myelination, regulation of presynaptic membrane function, and GABAergic function.

Brain Pathology: e.g. cortical atrophy, ventricular enlargement, reduced volume of various brain parts, abnormal laminar organization and orientation of neurons, decreased cellularity and cerebellar atrophy

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Neurodevelopmental Theory of Schizophrenia (Gupta & Kulhara, 2010) During adolescence, brain changes

normally include: Decrease in delta sleepDecrease in membrane synthesis Decreased volume of cortical gray

matterDecreased prefrontal metabolism

In schizophrenia, there are more pronounced decrements in the same parameters.

Feinberg (1983): this supports the possibility of an exaggeration of the normal process of synaptic pruning that occurs in schizophrenia during adolescence .

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Neurodevelopmental Theory of Schizophrenia:

Models (Corroon, 2005)The early neurodevelopmental

model: fixed lesion from early life interacts with normal neurodevelopment occurring later, lying dormant until the brain matures sufficiently to call into operation the damaged systems (Murray & Lewis, 1987).

The late neurodevelopmental model: schizophrenia may result from an abnormality in peri-adolescent synaptic pruning (Feinberg, 1983).

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Neurodevelopmental Theory of Schizophrenia:

“2-hit” model (Fatemi & Folsom, 2009) Keshavan and Hogarty (1999):

maldevelopment in schizophrenia takes place during 2 critical time points (early brain development and adolescence): Early developmental insults may lead to

dysfunction of specific neural networks that would account for premorbid signs

At adolescence, excessive synaptic pruning and loss of plasticity may account for the emergence of symptoms.

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Glutmate and Neurodevelopmental Theory of

Schizophrenia

NMDA receptors are a critical component of developmental processes during adolescence (Moghaddam, 2005).

This includes: development of neural pathwaysNeural migration Neural survivalNeural plasticity Neural pruning of cortical connections04/12/2023

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Glutmate and Neurodevelopmental Theory of

SchizophreniaStahl (2009): suggests that

Glutamate excitotoxicity first facilitates the neurodevelopmental disorder in adolescence.

Later, this results in a chronic state of Glutamate hypofunctioning which maintains the schizophrenic pathology in later stages.

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(3) The Glutamate Excitotoxicity as part of the

Neurodedegenarative Model of Schizophrenia

The excessive apoptosis theory

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Glutamate and Neurodegenerative Model of

Schizophrenia (Woods, 1998) Kraeplin and others believed that Schizophrenia is

caused by a form of progressive neuronal degeneration characterized by earlier onset than that seen with previously described entities, such as Huntington's disease or Alzheimer's disease > Dementia praecox

However, the neurodegenerative theory was opposed by the neurodevelopmental theory: 1) Most of the brain pathology in schizophrenia starts in

early adulthood2) No evidence of necrosis 3) There is no neurochemical explanation for

neurodegeneration Theory was later supported by the discoveries

about apoptosis and glutamate system. 36

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Glutamate and Neurodegenerative Model of

Schizophrenia (Glantz et al, 2006; Jarskog et al, 2005)

The neurostructural changes in schizophrenia have led to the hypothesis that apoptosis (programmed cell death) may contribute to the pathophysiology of schizophrenia.

Such changes include:Reduced neuropils (region between neuronal

cell bodies in the gray matter) and reductions of neurons.

Neuroimaging data > progressive loss of cortical grey matter in schizophrenia .

Postmortem studies: markers of apoptosis and levels of apoptotic proteins indicate > increased apoptotic vulnerability.

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Glutamate and Neurodegenerative Model of

Schizophrenia Again, glutamate is the main factor

involved in apoptosis (Stahl, 2009):High concentrations of glutamate accumulate

in the brain are thought to be involved in the aetiology of a number of neurodegenerative disorders including Alzheimer's disease (Coyle & Puttfarcken, 1993; Lipton & Rosenberg, 1994;).

A number of invitro studies > at high concentrations, glutamate is a potent neurotoxin capable of destroying neurons by apoptosis (Behl et al. 1995; Zhang & Bhavnani, 2003).04/12/2023

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Mg2+ Glutamate Calcium

AMPA*receptor

Presynaptic neurone

Postsynapticneurone

NMDAreceptor

Na+

[Ca2+]

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Conclusion of Glutmate role in Schizophrenia

Both glutamate hypoactivity as well as hyperactivity contribute to the pathology of schizophrenia (Stahl, 2009).

Gupta & Kulhara (2010) suggested that:Schizophrenia cannot be explained by a

single process of development or degeneration.

Research evidence exists for degeneration as well as developmental disorders.

The glutamatergic hypothesis bridges the gap between development and neurodegeneration in schizophrenia > "three hit hypothesis" (Keshavan, 1999).

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Clinical and pathological stages of schizophrenia (Gupta & Kulhara, 2010)

                                                                                                                                                                                                                               

 

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Glutamate Linked Treatments

of Schizophrenia

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Glutamate Linked Treatments of Schizophrenia:

Three classes of medications: 1. NMDA partial antagonists (early stage

schizophrenia)2. NMDA partial agonists (later stage

schizophrenia): - Glycine co-agonists- Glycine transporters inhibitors

3. NMDA modulators- mGlu autoreceptors co-agonists- Minocycline

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(1) NMDA Partial Antagonists: (Stahl, 2009)

To treat excitotoxicity in early stage. They include:

1. PCP and Ketamine: highly schizophrenogenic

2. NMDA partial antagonists e.g. memantine (already used in Alzheimer)

3. Drugs which block presynaptic release of glutamate e.g. Lamotrigine, gabapentin and pregabalin.

4. Anti-free radicals drugs e.g. vitamin E and experimental agents called lazaroids (so-named because they purport to raise neurons from the dead, like the biblical Lazarus).

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(2) NMDA Partial Agonists“Glycine co-agonists”

ΩTo treat glutamate hypofunctioning in later stages of schiz.

ΩThey act as agonists at the allosteric glycine receptor site of the NMDA complex (glycine co-agonists) as a way to avoid causing glutamate neurotoxicity Chaves et al. (2009).

ΩTwo ways to this:04/12/2023

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i. Glycine agonists to activate glycine site on the NMDA receptors as indirect way to potentiate the glutamte effect.

e.g. glycine, d-serine, d-alanine and d-cycloserine.

Provisional studies are promising. Research is still going on, using stronger agonists.

ii. Glycine transporters inhibitors (GlyT1 inhibitirs): e.g. sarcosine > promising remedy for negative symptoms of schizophrenia (Chaves et al, 2009) (Stahl, 2009).

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(3) NMDA ModulatorsmGlu autoreceptors co-agonists

Wieronska and Pilc (2009): mGlu receptors are the ideal target for medication (co-agonists) e.g. methionine amide.

Mechanisms of action are not quite clear. mGluR2/3 are mainly autoreceptors that

prevent glutamate release. The final result is enhancing glutamate

activity (?????).

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NMDA Modulators: mGlu2/3 autoreceptors co-

agonists They reverse the effects of PCP and

Ketamine in animals (Stahl, 2009) Some studies > methionine amide:

effective against + ve and - ve symptoms of schizophrenia (Moghaddam, 2005).

A RCT > after four weeks of treatment, an agonist for the mGluR2/3 (LY404039 ) has similar efficacy as Olanzapine in ameliorating positive and negative symptoms of schizophrenia (Patil et al., 2007).

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NMDA Modulators: Minocycline

(Chaves et al, 2009) Second-generation tetracycline with a

broad spectrum of antimicrobial activities and anti-inflammatory properties

Latest studies suggest that it is related to the glutamatergic system: minocycline reversed several NMDA antagonist effects in animal studies and showed good results in the treatment of patients with schizophrenia

Has neuroprotective effects in several animal and human models of neurological diseases, including Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and ischemia

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(Ellenbroek, 2012)

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Comments Glutamate hypothesis is a welcome addition but it

is not well developed yet, many issues need clarification:

1) Interactions between glutamate system, glycine

system, monoamines and other systems.

2) Glutamate linked drugs would be used in treatment of

schizophrenia with possible effects on depression,

anxiety, epilepsy, etc

3) Glutamate excitotoxicity and NMDA hypofunctioning in

schizophrenia is not clear.

4) Why mGlu2/3R agonists can enhance glutamate

activities despite of the fact that they should be

reducing the release of glutamate??????04/12/2023

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Comments We need to avoid the dopamine

mistake:i. Could it be over simplistic to attribute a major

illness to the mere quantitative increase or decrease of one chemical transmitter?

ii. Could it be over simplistic to assume that schizophrenia is a one illness with a one neurochemical pathology.

iii. Is possible that glutamate theory is a theory of something else e.g. neuronal excitability rather than schizophrenia theory. This would be similar to the argument that dopamine theory is a theory of psychosis not of schizophrenia? 04/12/2023

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Thank U

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