1
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
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
04/12/2023
3
(I) The Glutamate SystemL-Glutamate: “the king of neurotransmission”
04/12/2023
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.04/12/2023
5
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
04/12/2023
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 eight subgroups: (mGlu1-mGlu8).
04/12/2023
9
Metabotropic Glutamate Receptors
04/12/2023
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
04/12/2023
(1) NMDA Receptors Hypofunction Hypothesis of Schizophrenia:The Glutamate theory vs. the
Dopamine theory in schizophrenia
1104/12/2023
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.
04/12/2023
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 al., 1994;
Lahti et al., 1995).
04/12/2023
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).
04/12/2023
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).
04/12/2023
The Glutamate theory vs.
the Dopamine theory in
schizophrenia
1604/12/2023
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
04/12/2023
18
The DA Hypothesis of Schizophrenia: Positive Symptoms
04/12/2023
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.
04/12/2023
20
The DA Hypothesis of Schizophrenia: Negative, Cognitive, and Affective Symptoms
04/12/2023
21
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.
04/12/2023
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”.
04/12/2023
2304/12/2023
24
Role of Glutamate in the Mesocortical System
04/12/2023
25
Role of Glutamate in the Mesolimbic System
04/12/2023
26
(2) The Glutamate Excitotoxicity as part of the Neurodevelopmental Theory
of Schizophrenia
The excessive pruning theory
04/12/2023
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. 04/12/2023
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.
04/12/2023
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
04/12/2023
30
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 .
04/12/2023
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).
04/12/2023
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 emergence of symptoms.
04/12/2023
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 pathwaysNeural migration Neural survivalNeural plasticity Neural pruning of cortical connections04/12/2023
34
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.
04/12/2023
35
(3) The Glutamate Excitotoxicity as part of the
Neurodedegenarative Model of Schizophrenia
The excessive apoptosis theory
04/12/2023
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
04/12/2023
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.
04/12/2023
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).04/12/2023
3904/12/2023
Mg2+ Glutamate Calcium
AMPA*receptor
Presynaptic neurone
Postsynapticneurone
NMDAreceptor
Na+
[Ca2+]
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).
04/12/2023
41
Clinical and pathological stages of schizophrenia (Gupta & Kulhara, 2010)
04/12/2023
42
Glutamate Linked Treatments
of Schizophrenia
04/12/2023
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
04/12/2023
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).
04/12/2023
45
(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
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).
04/12/2023
4704/12/2023
48
(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 (?????).
04/12/2023
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).
04/12/2023
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
04/12/2023
5104/12/2023
(Ellenbroek, 2012)
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??????04/12/2023
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? 04/12/2023
54
Thank U
04/12/2023