Glutamate 33

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The Glutamate Hypothesis and The Glutamate Linked

Treatments of

Schizophrenia

Dr Khalid MansourLocum Consultant Psychiatrist

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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 Cerebral Glutamate Hypofunctioning Theory Cerebellar Glutamate Hypofunctioning Theory

b- The Glutamate Neurodevelopmental Theory

c- The Glutamate Neurodedegenarative Theory

(III) Glutamate Linked Treatments of Schizophrenia

(IV) Glutamate Theory and New Trends in Molecular Medicine

The Glutamate (Glutamic Acid)“the king of Neurotransmission”

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The Glutamate System

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The Glutamate System: (Moghaddam, 2005) Major excitatory

neurotransmitter and the most prevalent in the brain.

Nearly in 50% of the neurons in the brain.

In mammalians‘ brains: balanced with GABA (main inhibitory chemical transmitter).

Both transmitters influence almost every other chemical transmitter and brain areas.

Possible Therapeutic Applications (MRC Centre for Synaptic Plasticity 2010)

Multifacet ischemia, Epilepsy, Parkinson's disease, Alzheimer’s

disease, Hyperalgesia, Multiple Sclerosis,

Diabetes, Schizophrenia

Anxiety, Depression, etc.

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Glutamate Receptors: (MRC Centre for Synaptic Plasticity 2010)

Two classes of receptors in both neurones and glial cells:

Ionotropic receptors (Ligand gated ion channels): Four groups of receptors AMPA, NMDA, Kinate & Delta

Metabotropic receptors (G-protein coupled): 3 groups & 8 subgroups: (mGlu1 - mGlu8).

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Glutamate receptors

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NMDA receptor is distinct in two ways: First, it is both ligand-gated and voltage-dependent; second, it requires co-activation by two ligands - glutamate and glycine (Rang et al, July 2010).

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Functions of Glutamatergic Receptors and Transporters (Swanson et

al, 2005) The Ionotropic receptors: NMDA, kainate and AMPA mediate

fast receptor transmission neuronal plasticity Pruning Apoptosis

The metabotropic glutamate receptors (mGlu1 - mGlu8) modulate:

neurotransmitter (Glutamate) release postsynaptic excitability.

The vesicular transporters (vGluT1 and vGluT2) load glutamate into vesicles presynaptically. The glutamate transporters (EAAT1–5) are thought to mediate the uptake of glutamate and therefore termination of synaptic transmission.

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NMDA Hypofunction Hypothesis of Schizophrenia:

(I) The Involvement of the Glutamate System in

schizophrenia

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Glutamate system and schizophrenia (Moghaddam, 2005)

(1) The idea of a glutamatergic abnormality in schizophrenia was first proposed by Kim and colleagues in 1980: low cerebrospinal fluid (CSF) glutamate levels in patients with schizophrenia.

(2) Studies about Antiglutamatergic substances:Phencyclidine (PCP) or ketamine produces "schizophrenia-like" symptoms in healthy individuals and profoundly 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 (Moghaddam, 2005)(3) Genetic studies: The majority of the genes that have

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

(4) Postmortem receptors studies: Postmortem 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 (Moghaddam, 2005)

(5) Postmortem enzymes studies: Levels of amino acids N-acethylaspartate

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

(6) Brain imaging studies: Recent imaging studies using a novel SPECT

tracer for the NMDA receptor (123I)CNS-1261 (Pilowsky et al., 2005) have reported reduced NMDA receptor binding in the hippocampus of medication-free patients.

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(II) The Glutamate theory vs the Dopamine theory in

schizophrenia

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Dopamine Theory: Supportive Evidence1. Drugs that increase dopamine, such

as amphetamine and cocaine, can cause psychosis.

2. Antidopaminergic drugs can improve psychosis.

3. Neurophysiological studies > identifiable mechanism: over-activity in the mesolimbic dopamine pathway could be the mediator of positive symptoms of schizophrenia such as delusions and hallucinations.

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Dopamine Theory: problems

It explains only positive symptoms not negative symptoms of schizophrenia.

Anti-dopamenergic drugs frequently: 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

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.

CONCLUSION: DA theory is a “psychosis theory” more

than it is a “schizophrenia theory”.

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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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The Negative, Cognitive, and Affective Symptoms of Schiz & DA

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Cerebral Glutamate Hypofunctioning Theory: Another

golden triad1. Antiglutamatergic drugs e.g. PCP and Ketamine > NMDA receptors hypofunctional > psychosis

Positive symptoms (delusion and hallucination), Negative symptoms (avolition, apathy, and blunted

affect), Cognitive symptoms (deficits in attention, memory,

and abstract reasoning) 2. Glutamate linked drugs seem, so far, to

improve both positive and negative symptoms of schizophrenia (not fully proven yet)

3. Neurophysiological studies > a better identifiable mechanism: hypofunction of NMDA receptors could better explain the negative, cognitive and affective symptoms of schizophrenia.

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The neurophysiological changes in schizophrenia

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Role of Glutamate in the Mesolimbic System

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Role of Glutamate in the Mesocortical System

Cerebellar Glutamate Hypofunctioning

Theory:

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Andreasen et al (1998): Cognitive Dysmetria Theory of Schizophrenia The Cortico-Cerebellar-Thalamo-Cortical circuit is

dysfunctional in schizophrenia > poor mental coordination > (Cognitive Dysmetria) > Schizophrenia.

Yeganeh-Doost et al, 2011: hypofunctioning of the NMDA receptors in the cerebellum > cognitive dysmetria > schizophrenia

Problems: ? Yeganeh-Doost study not repeated and Andreasen theory not widly accepted.

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Cerebellar Glutamate Hypofunctioning Theory: (Yeganeh-

Doost et al, 2011)

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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 Theories 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).

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

The cause of the brain lesion is postulated to be either of abnormal genes, which impair brain development, or from some foetal or neonatal adversity.

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Neurodevelopmental Theories 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.

Obstetric and perinatal complications : e.g., 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 Theories of Schizophrenia: Evidence (Fatemi & Folsom, 2009)

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

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Neurodevelopmental Theories of Schizophrenia: Evidence (Gupta &

Kulhara, 2010) During adolescence, brain changes normally include: Decrease in delta sleep Decrease in membrane synthesis Decreased volume of cortical gray matter Decreased prefrontal metabolism

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

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Neurodevelopmental Theories of Schizophrenia: Models (Corroon, 2005) (1) The Early Neurodevelopmental

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

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

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Neurodevelopmental Theories of Schizophrenia:

(Fatemi & Folsom, 2009) (3) “2-hit” model (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 System and Neurodevelopmental Theories

of Schizophrenia

1. Necrosis theory2. Apoptosis theory

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Glutmate and Neurodevelopmental Theories of Schizophrenia

“NMDA receptors” is a critical component of developmental processes during adolescence (Moghaddam, 2005). This includes: Development of neural pathways Neural migration, Neural survival, Neural plasticity Neural pruning of cortical connections

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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 > “Dementia praecox” (Necrosis Theory)

Later studies showed high association with: cortical atrophy, ventricular enlargement, reduced volume of various brain parts, abnormal laminar organization and orientation of

neurons, decreased cellularity and cerebellar atrophy

However > no evidence of Necrosis in early adulthood; only late adulthood.

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Glutamate and Neurodegenerative Model of Schizophrenia (Woods, 1998;

Benes, 2004; Jarskog, 2005; Glantz, 2006) (Apoptosis Theory)

• Some studies supported the neurodegeneration theory by the discoveries about Apoptosis in schizophrenia

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

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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 in-vitro studies > at high concentrations, glutamate is a potent neurotoxin capable of destroying neurons via apoptosis (Behl et al. 1995; Zhang & Bhavnani, 2003).

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(1)Glutamate Hypofunctioning Theory vs Glutamate Neurodevelopmental

Theories of Schizophrenia

1. Two hit theory2. Three hit theory

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(1)Glutamate Hypofunctioning Theory vs the Neurodevelopmental Theories of Schizophrenia Stahl (2009): suggests that Glutamate

excitotoxicity in adolescence > apoptosis > neurodevelopmental disorder in adolescence.

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

“Two Hit Hypothesis”

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Glutamate Hypofunctioning Theory vs the Neurodevelopmental Theories of Schizophrenia 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 developmental abnormalities and differnt forms of neurodegeneration in schizophrenia > “Three Hit Hypothesis" (Keshavan, 1999).

? Apoptosis > Glutamate hypofunctioning > Necrosis.

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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 &

late stages in schizophrenia)2. NMDA partial agonists (midle stages

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

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

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(1) NMDA Partial Antagonists:To treat excitotoxicity in early and late

stage: 1. PCP and Ketamine > highly schizophrenogenic 2. NMDA partial antagonists e.g. Memantine

(already used in Alzheimer) (Lieberman, 2008; Krivoy et al, 2008; De Lucina et al, 2009)

3. Drugs which block presynaptic release of glutamate e.g. Lamotrigine, gabapentin and pregabalin (Tiihonen et al, 2003; Stahl, 2004; Gabriel, 2010).

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) (Stahl, 2009)

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NMDA Partial Agonists: glycine co-agonistsTo treat glutamate hypofunctioning in middle

stages of schiz > without causing neurotoxicity.

1. Glycine co-agonists (Chaves et al,2009) 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

2. Glycine transporters inhibitors (GlyT1 inhibitirs): e.g. sarcosine > promising remedy for negative symptoms of schizophrenia

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NMDA Modulators: mGlu2/3 autoreceptors co-agonists Wieronska and Pilc (2009): mGlu receptors as

the ideal target for medication especially if using the mGlu co-agonists e.g. methionine amide.

They reverse the effects of PCP and Ketamine in animals (Stahl, 2009)

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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Metabotropic glutamate receptors

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NMDA Modulators: Minocycline (Chaves et al, 2009) Second-generation tetracycline with

anti-inflammatory and neuroprotective properties.

Neuroprotective effects in several animal and human models of Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and ischemia

Reversed several NMDA antagonist effects in animal studies

Showed good provisional results in the treatment of patients with schizophrenia.

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1. Schizophrenia has numerous genetic, biological (non-genetic) and environmental factors.

2. Abnormal genetic or molecular mechanisms >120 discovered so far, associated with schizophrenia.

3. It is no longer realistic to have treatment base on a single or a small number of factors.

4. Schizophrenia seems now to be a brain maturational disorder that is caused by different genetic and none genetic factors; like in Learning Disabilities; any group of factors can cause the disorder.

5. The current tendency that individual schizophrenic patients are assessed for their own vulnerability factors and treated on those basis starting with personal genetic map for genetic effects.

6. Individualised treatment not single treatment for all.

Glutamate Theory and Recent Trends in Molecular Medicine

(Lieber Institute for Brain Development; Daniel Weinberger, 2013)

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Thank you

Health & Medicine

Glutamate 33