1. The Glutamate Hypothesis
and the Glutamate Linked
Treatments of Schizophrenia
Dr Mohamed Abdelghani
Ass. Lecturer Of Psychiatry
Zagazig Faculty Of Medicine
9/29/2012
Available at: http://www.slideshare.net/mabdelghani
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2. 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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3. (I) The Glutamate System
L-Glutamate: “the king of neurotransmission”
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4. 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.
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5. Possible therapeutic applications
(MRC Centre for Synaptic Plasticity 2010)
 Multifacet ischemia  Diabetes
 Epilepsy  MultipleSclerosis
 Parkinson's disease  Schizophrenia
 Alzheimer’s disease  Anxiety
 Hyperalgesia
 Depression
 Others
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6. 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
9/29/2012 eight subgroups: (mGlu1-mGlu8).
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9. Metabotropic Glutamate Receptors
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10. (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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11. (1) NMDA Receptors
Hypofunction Hypothesis
of Schizophrenia:
The Glutamate theory vs. the
Dopamine theory in schizophrenia
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12. 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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13. 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
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al., 1994; Lahti et al., 1995).
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14. 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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15. 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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16. The Glutamate theory
vs.
the Dopamine theory
in
schizophrenia
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17. 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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18. The DA Hypothesis of Schizophrenia: Positive Symptoms
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19. 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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20. The DA Hypothesis of Schizophrenia: Negative, Cognitive, and Affective Symptoms
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21. Dopamine Theory: Problems
 Itexplains 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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22. 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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23. 9/29/2012
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24. Role of Glutamate in the Mesocortical System
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25. Role of Glutamate in the Mesolimbic System
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26. (2) The Glutamate Excitotoxicity
as part of the
Neurodevelopmental Theory of
Schizophrenia
The excessive pruning theory
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27. 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.
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28. 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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29. 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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30. Neurodevelopmental Theory of
Schizophrenia (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.
 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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31. 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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32. 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
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emergence of symptoms. 32

33. Glutmate and Neurodevelopmental
Theory of Schizophrenia
 NMDA receptors are 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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34. Glutmate and Neurodevelopmental
Theory of Schizophrenia
 Stahl (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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35. (3) The Glutamate
Excitotoxicity as part of the
Neurodedegenarative Model of
Schizophrenia
The excessive apoptosis theory
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36. 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
adulthood
2) No evidence of necrosis
3) There is no neurochemical explanation for neurodegeneration
 Theory was later supported by the discoveries about
apoptosis and glutamate system.
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37. 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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38. 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).
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39. AMPA*
receptor
Presynaptic Postsynaptic
neurone neurone
Na+
[Ca2+]
NMDA
receptor
Mg2+ Glutamate Calcium
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40. 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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41. Clinical and pathological stages of
schizophrenia (Gupta & Kulhara, 2010)
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42. Glutamate Linked
Treatments
of
Schizophrenia
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43. 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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44. (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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45. (2) NMDA Partial Agonists
“Glycine co-agonists”
Ω To treat glutamate hypofunctioning in
later stages of schiz.
Ω They 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).
Ω Two ways to this:
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46. 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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48. (3) NMDA Modulators
mGlu 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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49. 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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50. 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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51. (Ellenbroek, 2012)
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52. 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??????
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53. 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?
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54. Thank U
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