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The Glutamate Hypothesis of
Schizophrenia
Dr Khalid Mansour
Consultant Psychiatrist
Priory Hospital Cefn Carnau
October 2015

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The Glutamate System: (Moghaddam, 2005)
 A food substance since 19 century.
 A neurotransmitter in insect studies in the early
1960s.
 Main excitatory neurotransmitter and the most
prevalent in the brain > nearly 50%.
 In mammalians‘ brains: balanced with GABA
(main inhibitory chemical transmitter).
 Both transmitters influence almost every other
chemical transmitter and brain areas.
 kim and colleagues in 1981: Glutamatergic
abnormality in schizophrenia
 Synaptic plasticity.
 Anti NMDA-R Encephalitis

POSSIBLE THERAPEUTIC APPLICATIONS
(MRC CENTRE FOR SYNAPTIC PLASTICITY 2010)
 Ischemia
 Epilepsy
 Parkinson's disease
 Hyperalgesia
 Multiple Sclerosis
 Huntington's disease
 Rasmussen's
encephalitis
 Glaucoma
 Nonketotic
hyperglycinemia 3
 Schizophrenia
 ADHD
 Autism
 Anxiety
 Depression
 OCD
 Alzheimer’s
disease
 Drug Addiction
 Wernicke's
encephalopathy

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GLUTAMATE SYSTEM AND
SCHIZOPHRENIA
1. NMDA-R Hypofunctioning Theory
 The Glutamate theory vs the Dopamine theory in schizophrenia
 Cerebellar Glutamate Hypofunctioning Theory
 The anti NMDA-R Antibodies Encephalitis and psychosis.
1. The Glutamate Neurodevelopmental
Theory
2. The Glutamate Neurodedegenarative
Theory
3. Glutamate Linked Treatments of
Schizophrenia

The Glutamate System
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(Stahl, 2009)

The Glutamate System
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GLUTAMATE RECEPTORS:
(MRC CENTRE FOR SYNAPTIC PLASTICITY 2010)

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Glutamate Related Cellular Structures
(Swanson et al, 2005)
Receptors:
Ionotropic receptors: NMDA, kainate and AMPA
mediate
 Fast receptor transmission
 neuronal plasticity
 Pruning
 apoptosis
Metabotropic glutamate receptors (mglu1 - mglu8)
modulate:
 Neurotransmitter (glutamate) release
 Postsynaptic excitability.
Vesicular Transporters (vGluT1 and vGluT2)
Load glutamate into vesicles presynaptically.
Glutamate Transporters (EAAT1–5)
Reuptake of glutamate and therefore termination of
synaptic transmission.

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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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GLUTAMATE RECEPTORS

Post Synaptic Density (PSD)

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(I) The Involvement of 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 1981 > low CSF glutamate
levels in schizophrenia.
(2) Studies about Antiglutamatergic
substances:
Phencyclidine (PCP) or ketamine produces
"schizophrenia-like" symptoms in healthy
individuals and profoundly exacerbates pre-
existing schizophrenia (Lodge & Anis, 1982, Tricklebank
et al, 1989, 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 genes associated with
schizophrenia > linked to glutamate
system (Harrison et al., 2003; Moghaddam, 2003).
(4) Postmortem Receptors Studies:
 Schizophrenic subjects > changes in
glutamate receptor binding, transcription
and subunit protein expression in
prefrontal cortex, thalamus, and
hippocampus (Clinton and Meador-Woodruff,
2004).

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GLUTAMATE SYSTEM AND SCHIZOPHRENIA
(MOGHADDAM, 2005)
(5) Postmortem Enzymes Studies:
 Altered levels of NAA (amino acids N-
acethylaspartate) and NAAG (N-
acethylaspartylglutamate), and activity of the
enzyme that cleaves NAA to NAAG and
glutamate > in CSF and postmortem
tissues in schizophrenia (Tsai et al, 1995).
(6) Brain Imaging Studies:
 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:
(Stahl, 2009)

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DOPAMINE THEORY: SUPPORTIVE EVIDENCE
1. 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 > positive symptoms of
schizophrenia e.g. delusions and
hallucinations.

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DOPAMINE THEORY: PROBLEMS
“Psychosis Theory vs. Schizophrenia Theory”
 Explains +ve not –ve symptoms.
 Anti-dopamenergic drugs frequently:
 make -ve symptoms worse
 induce -ve symptoms in healthy people.
 Atypical antipsychotic drugs e.g. Clozapine
(with weaker anti-dopaminergic activity) >
better anti-schizophrenic drugs.
 Under-activity in the meso-cortical
dopamine pathway > negative symptoms
of schizophrenia > not over-activity.

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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
(Stahl, 2009)

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The neurophysiological changes in schizophrenia(Stahl, 2009)

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(1) NMDA-R Hypofunction
Hypothesis of Schizophrenia:
(Stahl, 2009)

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A- Cerebral Glutamate Hypofunctioning
Theory
1. 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)
1. Glutamate linked drugs seem to improve both
positive and negative symptoms of
schizophrenia (not fully proven yet)
2. Neurophysiological studies > a better identifiable
mechanism: hypofunction of NMDA receptors
better explain the negative, cognitive and
affective symptoms of schizophrenia.

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ROLE OF GLUTAMATE IN THE MESOLIMBIC SYSTEM
(Stahl, 2009)

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ROLE OF GLUTAMATE IN THE MESOCORTICAL SYSTEM
(Stahl, 2009)

B- CEREBELLAR GLUTAMATE
HYPOFUNCTIONING THEORY:
(YEGANEH-DOOST ET AL, 2011)
 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. 27

Problems with NMDA Hypofunctioning Theory
1- Glutamate Receptor Anomalies in
Schizophrenia:
Although some reports > reduction in
glutamate receptors in cortical regions of
schizophrenia patients (Vrajová et al, 2010; Weickert et al,
2013), several other studies found no substantial
differences with controls (Clinton et al, 2006;
McCullumsmith et al, 2007).
2- No medications.
3- Why only schizophrenia ?!!!

Modified NMDA Hypofunctioning Theory
The Postsynaptic Density (PSD): (Iasevoli et al, 2014)
Some PSD proteins, are implicated in severe
behavioral disorders, including schizophrenia.
PSD proteins may represent potential targets for new
molecular interventions in psychosis.
Portions implicated by some studies:
PSD-95 mRNA (Iasevoli et al, 2014)
scaffolding protein Shank (Iasevoli et al, 2014)
scaffold proteins Homer (Iasevoli et al, 2014)
DISC-1 (de Bartolomeis et al, 2014)
microRNA (de Bartolomeis et al, 2015)

Role of Post synaptic density (PSD) In
Schizophrenia (Iasevoli et al, 2014)

Anti-NMDA Receptor Antibody Encephalitis
 The most common cause of autoimmune encephalitis
after acute demyelinating encephalitis (Ambrose et al,
2010).
 Symptoms include: psychiatric, neurological and
other physical symptoms (Irani 2010).
 Significant association with psychiatric symotms
(Dalmau, 2008 (80%); Titulaer 2013 (65%).
 psychiatric symptoms include psychosis, mood
disorder and personality change, amnesia, confusion
(Irani 2010).
 Assertive Immunotherapy can resolve symptoms
including psychiatric symptomsis (Rickards et al, 2014).

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(2) The Glutamate
Neurodevelopmental Theory of
Schizophrenia:
The Excessive Synaptic Pruning Theory
(Stahl, 2009)

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Selemon & Zecevic, 2015

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NEURODEVELOPMENTAL THEORIES OF SCHIZOPHRENIA:
HISTORICAL EVIDENCE (FATEMI & FOLSOM, 2009)
High Associstion of Schizophrenia with:
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 haemorrhages, hypoxia, and
ischemic injuries and prenatal viral infections.
Murray et al, 1992: Early brain insult > affects brain
development > abnormalities in the mature brain
(Murray et al, 1992).
Kraeplin in the early 20th
century: suggested similar
theory.

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Neurodevelopmental Theories of
Schizophrenia: (FATEMI & FOLSOM, 2009)
Schizophrenia associated with:
Abnormal Brain Maturity Markers in
adolescence : e.g. proteins involved in early
neurons and glia migration, cell proliferation,
axonal outgrowth, synaptogenesis, and
apoptosis.
Genetics studies: various gene 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:
GLUTAMATE INVOLVEMENT EVIDENCE (GUPTA & KULHARA, 2010)
 “NMDA-R > critical component of
developmental processes during adolescence:
Development of neural pathways, Neural
migration, Neural survival, Neural plasticity &
Neural pruning of cortical connections
(Moghaddam, 2005; hayashi-takagi, 2010; dawson et al, 2015).
 An excessive pruning of the prefrontal cortico-
cortical, and cortico-subcortical synapses,
perhaps involving the excitatory glutamatergic
inputs to pyramidal neurons, may underlie
schizophrenia (keshavan et al, 1994; Faludi & Mirnics, 2011;
Boksa, 2012).

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(3) Glutmate System and
Neurodegenerative Theories of
Schizophrenia
A. Necrosis theory
B. Apoptosis theory

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Glutamate and Neurodegenerative Model of
Schizophrenia: Necrosis Theory (WOODS, 1998)
 Kraeplin and others believed that Schizophrenia is caused
by a form of progressive neuronal degeneration
characterizedby earlier onset > “Dementia praecox”
 Later studies showed high association with:
 Cerebral and cerebellar atrophy,
 Ventricular enlargement (johnstone et al, 1976),
 Reduced volume of various brain parts,
 Abnormal laminar organization and orientation of
neurons,
 Decreased cellularity.
 However > no evidence of necrosis (gliosis) in early
adulthood; only late adulthood.

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Glutamate and Neurodegenerative Model of
Schizophrenia: Apoptosis Theory
(Woods, 1998; Benes, 2004; Jarskog, 2005; Glantz, 2006; Gupta &
Kulhara, 2010)
• Above and other 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.
• Post mortem, neurochemical studies >
glutamate toxicity > graded apoptosis >
neurodegenerative changes without gliosis

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Glutamate Hypofunctioning Theory vs
Glutamate Neurotoxicity Theories of
Schizophrenia
1. Two hit theory
2. Three hit theory

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(1) The Two Hit Theory: Glutamate
Apoptosis then Hypofunctioning Theory
 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.

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(2) The Three Hit Theory: Glutamate Excessive
Pruning Then Hypofunctioning Then
Apoptosis:
Gupta & Kulhara (2010):
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
different forms of neurodegeneration in
schizophrenia > “Three Hit Hypothesis" (Keshavan,
1999).

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Glutamate Linked
Treatments of
Schizophrenia:

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EXPERIMENTAL 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
1.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-AGONISTS
To treat glutamate hypofunctioning in middle
stages of schiz > without causing neurotoxicity.
 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
 Glycine Transporters Inhibitors (GlyT1
Inhibitor): e.g. sarcosine > promising remedy
for negative symptoms of schizophrenia

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NMDA Modulators:
mGlu2/3 Autoreceptors Co-agonists
 Methionine Amide
 > effective against + ve and - ve symptoms
of schizophrenia (Moghaddam, 2005).
 > reverse the effects of PCP and Ketamine
in animals (Stahl, 2009)
 LY404039 (mGluR2/3 agonist) RCT > after
four weeks of treatment > 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 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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Some Conclusions

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What could be wrong with that?
 Over simplistic: One size fits for all.
 Partial, vague evidence.
 Does not explain why glutamate abnormalities do not
casue all other disorders with schiz.
 Does not explain why glutamate based treatments are
not used yet.
 It seems that any chemical transmitter if too high or too
low can induce psychotic reaction.
 How can both glutamate agonist and antagonists treat
schiz; what about opposit effects.
 Anti NMDA-R antibodies encephalitis do not cause only
psychosis or schizophrenia

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What is good about that what
 The theory is incomplete but not invalid.
 A step in the right direction
 Need more work.
 Schizophrenia is not a one thing anyway
(Lieberman & Koreen, 1993) and definitly has multiple
aetiologies and neuro-mechanisms.

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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;
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.
A Recent Trends in Molecular Medicine
(Lieber Institute for Brain Development; Daniel Weinberger, 2013)

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THANK YOU
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