SlideShare a Scribd company logo
1 of 54
Download to read offline
1
The Glutamate Hypothesis of
Schizophrenia
Dr Khalid Mansour
Consultant Psychiatrist
Priory Hospital Cefn Carnau
October 2015
2
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
4
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
5
6
(Stahl, 2009)
The Glutamate System
7
8
GLUTAMATE RECEPTORS:
(MRC CENTRE FOR SYNAPTIC PLASTICITY 2010)
9
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.
10
11
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).
12
GLUTAMATE RECEPTORS
Post Synaptic Density (PSD)
14
(I) The Involvement of Glutamate
System in Schizophrenia
15
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).
16
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).
17
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.
18
(II) The Glutamate Theory vs the
Dopamine Theory in Schizophrenia:
(Stahl, 2009)
19
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.
20
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.
21
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)
22
The neurophysiological changes in schizophrenia(Stahl, 2009)
23
(1) NMDA-R Hypofunction
Hypothesis of Schizophrenia:
(Stahl, 2009)
24
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.
25
ROLE OF GLUTAMATE IN THE MESOLIMBIC SYSTEM
(Stahl, 2009)
26
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).
32
(2) The Glutamate
Neurodevelopmental Theory of
Schizophrenia:
The Excessive Synaptic Pruning Theory
(Stahl, 2009)
33
Selemon & Zecevic, 2015
34
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.
35
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.
36
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).
37
(3) Glutmate System and
Neurodegenerative Theories of
Schizophrenia
A. Necrosis theory
B. Apoptosis theory
38
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.
39
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
40
41
Glutamate Hypofunctioning Theory vs
Glutamate Neurotoxicity Theories of
Schizophrenia
1. Two hit theory
2. Three hit theory
42
(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.
43
(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).
44
Glutamate Linked
Treatments of
Schizophrenia:
45
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
46
(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)
47
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
48
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).
49
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.
50
Some Conclusions
51
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
52
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.
53
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)
54
THANK YOU
Comments

More Related Content

What's hot

Newer atypical antipsychotic agents
Newer atypical antipsychotic agentsNewer atypical antipsychotic agents
Newer atypical antipsychotic agentsYashasree Poudwal
 
Dopamine hypothesis
Dopamine hypothesisDopamine hypothesis
Dopamine hypothesiskellula
 
Treatment of resistant depression
Treatment of resistant depressionTreatment of resistant depression
Treatment of resistant depressionHarsh shaH
 
ANTIDEPRESSANTS: All you need to know...by RxVichu! :)
ANTIDEPRESSANTS: All you need to know...by RxVichu! :)ANTIDEPRESSANTS: All you need to know...by RxVichu! :)
ANTIDEPRESSANTS: All you need to know...by RxVichu! :)RxVichuZ
 
Treatment of schizophrenia current issues and future possibilities
Treatment of schizophrenia  current issues and future possibilitiesTreatment of schizophrenia  current issues and future possibilities
Treatment of schizophrenia current issues and future possibilitiesDr Wasim
 
Neurotransmittter and role of dopamine in psychiatry
Neurotransmittter and role of dopamine in psychiatryNeurotransmittter and role of dopamine in psychiatry
Neurotransmittter and role of dopamine in psychiatryurvashi kumar
 
Anti psychotic drugs
Anti psychotic drugsAnti psychotic drugs
Anti psychotic drugsDr Renju Ravi
 
TREATMENT RESISTANT DEPRESSION
TREATMENT RESISTANT DEPRESSIONTREATMENT RESISTANT DEPRESSION
TREATMENT RESISTANT DEPRESSIONSubrata Naskar
 
John Kane - Treatment-Resistant Schizophrenia: New Guidelines on Diagnosis an...
John Kane - Treatment-Resistant Schizophrenia: New Guidelines on Diagnosis an...John Kane - Treatment-Resistant Schizophrenia: New Guidelines on Diagnosis an...
John Kane - Treatment-Resistant Schizophrenia: New Guidelines on Diagnosis an...wef
 
Dr Amit Chougule Recent advances in psychiatry
Dr Amit Chougule Recent advances in psychiatry Dr Amit Chougule Recent advances in psychiatry
Dr Amit Chougule Recent advances in psychiatry Dr. Amit Chougule
 
Dopamine
DopamineDopamine
DopamineSethu S
 
Serotonin and its role in psychiatry.pptx
Serotonin and its role in psychiatry.pptxSerotonin and its role in psychiatry.pptx
Serotonin and its role in psychiatry.pptxAdityaAgrawal238
 
The glutamate hypothesis and the glutamate linked treatments of schizophrenia
The glutamate hypothesis and the glutamate linked treatments of schizophreniaThe glutamate hypothesis and the glutamate linked treatments of schizophrenia
The glutamate hypothesis and the glutamate linked treatments of schizophreniaMohamed Abdelghani
 
Neuro-Psychiatric aspect of Diabetes Mellitus
Neuro-Psychiatric aspect of Diabetes MellitusNeuro-Psychiatric aspect of Diabetes Mellitus
Neuro-Psychiatric aspect of Diabetes MellitusDr.Jeet Nadpara
 

What's hot (20)

Newer atypical antipsychotic agents
Newer atypical antipsychotic agentsNewer atypical antipsychotic agents
Newer atypical antipsychotic agents
 
Catie
CatieCatie
Catie
 
Dopamine hypothesis
Dopamine hypothesisDopamine hypothesis
Dopamine hypothesis
 
Treatment of resistant depression
Treatment of resistant depressionTreatment of resistant depression
Treatment of resistant depression
 
ANTIDEPRESSANTS: All you need to know...by RxVichu! :)
ANTIDEPRESSANTS: All you need to know...by RxVichu! :)ANTIDEPRESSANTS: All you need to know...by RxVichu! :)
ANTIDEPRESSANTS: All you need to know...by RxVichu! :)
 
Antianxiety agents
Antianxiety agentsAntianxiety agents
Antianxiety agents
 
Treatment of schizophrenia current issues and future possibilities
Treatment of schizophrenia  current issues and future possibilitiesTreatment of schizophrenia  current issues and future possibilities
Treatment of schizophrenia current issues and future possibilities
 
Neurotransmittter and role of dopamine in psychiatry
Neurotransmittter and role of dopamine in psychiatryNeurotransmittter and role of dopamine in psychiatry
Neurotransmittter and role of dopamine in psychiatry
 
Anti psychotic drugs
Anti psychotic drugsAnti psychotic drugs
Anti psychotic drugs
 
Glutamate & schizophrenia
Glutamate & schizophreniaGlutamate & schizophrenia
Glutamate & schizophrenia
 
TREATMENT RESISTANT DEPRESSION
TREATMENT RESISTANT DEPRESSIONTREATMENT RESISTANT DEPRESSION
TREATMENT RESISTANT DEPRESSION
 
Antidepressants
AntidepressantsAntidepressants
Antidepressants
 
John Kane - Treatment-Resistant Schizophrenia: New Guidelines on Diagnosis an...
John Kane - Treatment-Resistant Schizophrenia: New Guidelines on Diagnosis an...John Kane - Treatment-Resistant Schizophrenia: New Guidelines on Diagnosis an...
John Kane - Treatment-Resistant Schizophrenia: New Guidelines on Diagnosis an...
 
Antipsychotics - drdhriti
Antipsychotics - drdhritiAntipsychotics - drdhriti
Antipsychotics - drdhriti
 
Vortioxetine
VortioxetineVortioxetine
Vortioxetine
 
Dr Amit Chougule Recent advances in psychiatry
Dr Amit Chougule Recent advances in psychiatry Dr Amit Chougule Recent advances in psychiatry
Dr Amit Chougule Recent advances in psychiatry
 
Dopamine
DopamineDopamine
Dopamine
 
Serotonin and its role in psychiatry.pptx
Serotonin and its role in psychiatry.pptxSerotonin and its role in psychiatry.pptx
Serotonin and its role in psychiatry.pptx
 
The glutamate hypothesis and the glutamate linked treatments of schizophrenia
The glutamate hypothesis and the glutamate linked treatments of schizophreniaThe glutamate hypothesis and the glutamate linked treatments of schizophrenia
The glutamate hypothesis and the glutamate linked treatments of schizophrenia
 
Neuro-Psychiatric aspect of Diabetes Mellitus
Neuro-Psychiatric aspect of Diabetes MellitusNeuro-Psychiatric aspect of Diabetes Mellitus
Neuro-Psychiatric aspect of Diabetes Mellitus
 

Similar to Glutamate Hypothesis of Schizophrenia

Hans Jürgen-Current situation and future perspetives of antipsychotics in sch...
Hans Jürgen-Current situation and future perspetives of antipsychotics in sch...Hans Jürgen-Current situation and future perspetives of antipsychotics in sch...
Hans Jürgen-Current situation and future perspetives of antipsychotics in sch...Fundación Ramón Areces
 
Hanipsych, updates on neurobiology and neurotoxicity of depression
Hanipsych, updates on neurobiology and neurotoxicity of depressionHanipsych, updates on neurobiology and neurotoxicity of depression
Hanipsych, updates on neurobiology and neurotoxicity of depressionHani Hamed
 
Neuroleptics & Anxiolytics (Abstract)
Neuroleptics & Anxiolytics (Abstract)Neuroleptics & Anxiolytics (Abstract)
Neuroleptics & Anxiolytics (Abstract)Eneutron
 
Joelle_Petrei_Finished_Grant_2016
Joelle_Petrei_Finished_Grant_2016Joelle_Petrei_Finished_Grant_2016
Joelle_Petrei_Finished_Grant_2016Joelle Petrei
 
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...Dr. Rafael Higashi
 
Obssessive Compulsive Disorders
Obssessive Compulsive DisordersObssessive Compulsive Disorders
Obssessive Compulsive DisordersOla
 
Molecular Substrates of Drug Abuse in a Schizophrenic Population
Molecular Substrates of Drug Abuse in a Schizophrenic PopulationMolecular Substrates of Drug Abuse in a Schizophrenic Population
Molecular Substrates of Drug Abuse in a Schizophrenic PopulationAlan Lesselyong
 
The neurobiology and pharmacotherapy of bipolar
The neurobiology and pharmacotherapy of bipolarThe neurobiology and pharmacotherapy of bipolar
The neurobiology and pharmacotherapy of bipolarNick Stafford
 
74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...
74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...
74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...ICREA
 
Book role of plants, environmental toxins and physical neurotoxicological fac...
Book role of plants, environmental toxins and physical neurotoxicological fac...Book role of plants, environmental toxins and physical neurotoxicological fac...
Book role of plants, environmental toxins and physical neurotoxicological fac...M. Luisetto Pharm.D.Spec. Pharmacology
 
A Brief Description Of Schizophrenia
A Brief Description Of SchizophreniaA Brief Description Of Schizophrenia
A Brief Description Of SchizophreniaPeggy Johnson
 
Neurotransmitters Function
Neurotransmitters FunctionNeurotransmitters Function
Neurotransmitters FunctionKate Miller
 
3- Antipsychotic agents.ppt
3- Antipsychotic agents.ppt3- Antipsychotic agents.ppt
3- Antipsychotic agents.pptAshlynnElla3
 
Correlation of Neuropsycholgy and Schizophrenia.pdf
Correlation of Neuropsycholgy and Schizophrenia.pdfCorrelation of Neuropsycholgy and Schizophrenia.pdf
Correlation of Neuropsycholgy and Schizophrenia.pdfSHRISHTIKUNDU
 

Similar to Glutamate Hypothesis of Schizophrenia (20)

Hans Jürgen-Current situation and future perspetives of antipsychotics in sch...
Hans Jürgen-Current situation and future perspetives of antipsychotics in sch...Hans Jürgen-Current situation and future perspetives of antipsychotics in sch...
Hans Jürgen-Current situation and future perspetives of antipsychotics in sch...
 
Hanipsych, updates on neurobiology and neurotoxicity of depression
Hanipsych, updates on neurobiology and neurotoxicity of depressionHanipsych, updates on neurobiology and neurotoxicity of depression
Hanipsych, updates on neurobiology and neurotoxicity of depression
 
Neuroleptics & Anxiolytics (Abstract)
Neuroleptics & Anxiolytics (Abstract)Neuroleptics & Anxiolytics (Abstract)
Neuroleptics & Anxiolytics (Abstract)
 
Glutamate and schizophrenia
Glutamate and schizophreniaGlutamate and schizophrenia
Glutamate and schizophrenia
 
Schizophrenia
SchizophreniaSchizophrenia
Schizophrenia
 
Joelle_Petrei_Finished_Grant_2016
Joelle_Petrei_Finished_Grant_2016Joelle_Petrei_Finished_Grant_2016
Joelle_Petrei_Finished_Grant_2016
 
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
 
MEDICATION INDUCED MOVEMENT DISORDERS
MEDICATION INDUCED MOVEMENT DISORDERSMEDICATION INDUCED MOVEMENT DISORDERS
MEDICATION INDUCED MOVEMENT DISORDERS
 
Obssessive Compulsive Disorders
Obssessive Compulsive DisordersObssessive Compulsive Disorders
Obssessive Compulsive Disorders
 
Molecular Substrates of Drug Abuse in a Schizophrenic Population
Molecular Substrates of Drug Abuse in a Schizophrenic PopulationMolecular Substrates of Drug Abuse in a Schizophrenic Population
Molecular Substrates of Drug Abuse in a Schizophrenic Population
 
ZOO 400
ZOO 400ZOO 400
ZOO 400
 
The neurobiology and pharmacotherapy of bipolar
The neurobiology and pharmacotherapy of bipolarThe neurobiology and pharmacotherapy of bipolar
The neurobiology and pharmacotherapy of bipolar
 
74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...
74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...
74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathwa...
 
M.Sc Presentation
M.Sc PresentationM.Sc Presentation
M.Sc Presentation
 
MMcilwain_2015
MMcilwain_2015MMcilwain_2015
MMcilwain_2015
 
Book role of plants, environmental toxins and physical neurotoxicological fac...
Book role of plants, environmental toxins and physical neurotoxicological fac...Book role of plants, environmental toxins and physical neurotoxicological fac...
Book role of plants, environmental toxins and physical neurotoxicological fac...
 
A Brief Description Of Schizophrenia
A Brief Description Of SchizophreniaA Brief Description Of Schizophrenia
A Brief Description Of Schizophrenia
 
Neurotransmitters Function
Neurotransmitters FunctionNeurotransmitters Function
Neurotransmitters Function
 
3- Antipsychotic agents.ppt
3- Antipsychotic agents.ppt3- Antipsychotic agents.ppt
3- Antipsychotic agents.ppt
 
Correlation of Neuropsycholgy and Schizophrenia.pdf
Correlation of Neuropsycholgy and Schizophrenia.pdfCorrelation of Neuropsycholgy and Schizophrenia.pdf
Correlation of Neuropsycholgy and Schizophrenia.pdf
 

More from khalid mansour

Repetitive behaviour in autism: a neurobehavioural approach
Repetitive behaviour in autism: a neurobehavioural approach  Repetitive behaviour in autism: a neurobehavioural approach
Repetitive behaviour in autism: a neurobehavioural approach khalid mansour
 
Bi dimensional model of PD an attempt to foresee future of psychiatry 15
Bi dimensional model of PD an attempt to foresee future of  psychiatry  15Bi dimensional model of PD an attempt to foresee future of  psychiatry  15
Bi dimensional model of PD an attempt to foresee future of psychiatry 15khalid mansour
 
Autoimmune encephalitis 144
Autoimmune encephalitis 144Autoimmune encephalitis 144
Autoimmune encephalitis 144khalid mansour
 
Autoimmune encephalitis and psychiatry
Autoimmune encephalitis and psychiatry Autoimmune encephalitis and psychiatry
Autoimmune encephalitis and psychiatry khalid mansour
 
Understanding autism 444
Understanding autism 444Understanding autism 444
Understanding autism 444khalid mansour
 
Assessment of dd new 7
Assessment of dd new 7Assessment of dd new 7
Assessment of dd new 7khalid mansour
 
Clinical forums as means of marketing a service
Clinical forums as means of marketing a serviceClinical forums as means of marketing a service
Clinical forums as means of marketing a servicekhalid mansour
 
autistic traits in individuals with normal intelligence
autistic traits in individuals with normal intelligenceautistic traits in individuals with normal intelligence
autistic traits in individuals with normal intelligencekhalid mansour
 
Difference between mental disabilities and mental disorders 8
Difference between mental   disabilities and mental disorders 8Difference between mental   disabilities and mental disorders 8
Difference between mental disabilities and mental disorders 8khalid mansour
 

More from khalid mansour (18)

Fxs 43
Fxs 43Fxs 43
Fxs 43
 
Repetitive behaviour in autism: a neurobehavioural approach
Repetitive behaviour in autism: a neurobehavioural approach  Repetitive behaviour in autism: a neurobehavioural approach
Repetitive behaviour in autism: a neurobehavioural approach
 
Bi dimensional model of PD an attempt to foresee future of psychiatry 15
Bi dimensional model of PD an attempt to foresee future of  psychiatry  15Bi dimensional model of PD an attempt to foresee future of  psychiatry  15
Bi dimensional model of PD an attempt to foresee future of psychiatry 15
 
Autoimmune encephalitis 144
Autoimmune encephalitis 144Autoimmune encephalitis 144
Autoimmune encephalitis 144
 
Cerebellum 78
Cerebellum 78Cerebellum 78
Cerebellum 78
 
Autoimmune encephalitis and psychiatry
Autoimmune encephalitis and psychiatry Autoimmune encephalitis and psychiatry
Autoimmune encephalitis and psychiatry
 
Understanding autism 444
Understanding autism 444Understanding autism 444
Understanding autism 444
 
Cerebellum 66
Cerebellum 66Cerebellum 66
Cerebellum 66
 
Assessment of dd new 7
Assessment of dd new 7Assessment of dd new 7
Assessment of dd new 7
 
Clinical forums as means of marketing a service
Clinical forums as means of marketing a serviceClinical forums as means of marketing a service
Clinical forums as means of marketing a service
 
Fragile X Syndrome
Fragile X SyndromeFragile X Syndrome
Fragile X Syndrome
 
autistic traits in individuals with normal intelligence
autistic traits in individuals with normal intelligenceautistic traits in individuals with normal intelligence
autistic traits in individuals with normal intelligence
 
Bahrain paper 3
Bahrain paper 3Bahrain paper 3
Bahrain paper 3
 
Triune theory 3333
Triune theory 3333Triune theory 3333
Triune theory 3333
 
Tripartite 12
Tripartite 12Tripartite 12
Tripartite 12
 
Difference between mental disabilities and mental disorders 8
Difference between mental   disabilities and mental disorders 8Difference between mental   disabilities and mental disorders 8
Difference between mental disabilities and mental disorders 8
 
Fxs 35
Fxs 35Fxs 35
Fxs 35
 
Cerebellum 66
Cerebellum 66Cerebellum 66
Cerebellum 66
 

Recently uploaded

Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptxBreast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptxNaveenkumar267201
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...Shubhanshu Gaurav
 
Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024Peter Embi
 
pA2 value, Schild plot and pD2 values- applications in pharmacology
pA2 value, Schild plot and pD2 values- applications in pharmacologypA2 value, Schild plot and pD2 values- applications in pharmacology
pA2 value, Schild plot and pD2 values- applications in pharmacologyDeepakDaniel9
 
Using Data Visualization in Public Health Communications
Using Data Visualization in Public Health CommunicationsUsing Data Visualization in Public Health Communications
Using Data Visualization in Public Health Communicationskatiequigley33
 
Adenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosisAdenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosisSujoy Dasgupta
 
BENIGN BREAST DISEASE
BENIGN BREAST DISEASE BENIGN BREAST DISEASE
BENIGN BREAST DISEASE Mamatha Lakka
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets barmohitRahangdale
 
High-Performance Thin-Layer Chromatography (HPTLC)
High-Performance Thin-Layer Chromatography (HPTLC)High-Performance Thin-Layer Chromatography (HPTLC)
High-Performance Thin-Layer Chromatography (HPTLC)kishan singh tomar
 
Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024EwoutSteyerberg1
 
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptxANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptxWINCY THIRUMURUGAN
 
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.aarjukhadka22
 
blood bank management system project report
blood bank management system project reportblood bank management system project report
blood bank management system project reportNARMADAPETROLEUMGAS
 
power point presentation of Clinical evaluation of strabismus
power point presentation of Clinical evaluation  of strabismuspower point presentation of Clinical evaluation  of strabismus
power point presentation of Clinical evaluation of strabismusChandrasekar Reddy
 
AUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsAUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsMedicoseAcademics
 
CPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentCPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentsaileshpanda05
 
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdfPAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdfDolisha Warbi
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdfHongBiThi1
 

Recently uploaded (20)

Rheumatoid arthritis Part 1, case based approach with application of the late...
Rheumatoid arthritis Part 1, case based approach with application of the late...Rheumatoid arthritis Part 1, case based approach with application of the late...
Rheumatoid arthritis Part 1, case based approach with application of the late...
 
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptxBreast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
Breast cancer -ONCO IN MEDICAL AND SURGICAL NURSING.pptx
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
 
Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024
 
pA2 value, Schild plot and pD2 values- applications in pharmacology
pA2 value, Schild plot and pD2 values- applications in pharmacologypA2 value, Schild plot and pD2 values- applications in pharmacology
pA2 value, Schild plot and pD2 values- applications in pharmacology
 
Biologic therapy ice breaking in rheumatology, Case based approach with appli...
Biologic therapy ice breaking in rheumatology, Case based approach with appli...Biologic therapy ice breaking in rheumatology, Case based approach with appli...
Biologic therapy ice breaking in rheumatology, Case based approach with appli...
 
Using Data Visualization in Public Health Communications
Using Data Visualization in Public Health CommunicationsUsing Data Visualization in Public Health Communications
Using Data Visualization in Public Health Communications
 
Adenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosisAdenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosis
 
BENIGN BREAST DISEASE
BENIGN BREAST DISEASE BENIGN BREAST DISEASE
BENIGN BREAST DISEASE
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets bar
 
High-Performance Thin-Layer Chromatography (HPTLC)
High-Performance Thin-Layer Chromatography (HPTLC)High-Performance Thin-Layer Chromatography (HPTLC)
High-Performance Thin-Layer Chromatography (HPTLC)
 
Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024Trustworthiness of AI based predictions Aachen 2024
Trustworthiness of AI based predictions Aachen 2024
 
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptxANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
 
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
Bulimia nervosa ( Eating Disorders) Mental Health Nursing.
 
blood bank management system project report
blood bank management system project reportblood bank management system project report
blood bank management system project report
 
power point presentation of Clinical evaluation of strabismus
power point presentation of Clinical evaluation  of strabismuspower point presentation of Clinical evaluation  of strabismus
power point presentation of Clinical evaluation of strabismus
 
AUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsAUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functions
 
CPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentCPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing student
 
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdfPAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
PAIN/CLASSIFICATION AND MANAGEMENT OF PAIN.pdf
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
 

Glutamate Hypothesis of Schizophrenia

  • 1. 1 The Glutamate Hypothesis of Schizophrenia Dr Khalid Mansour Consultant Psychiatrist Priory Hospital Cefn Carnau October 2015
  • 2. 2 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
  • 3. 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
  • 4. 4 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
  • 8. 8 GLUTAMATE RECEPTORS: (MRC CENTRE FOR SYNAPTIC PLASTICITY 2010)
  • 9. 9 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.
  • 10. 10
  • 11. 11 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).
  • 14. 14 (I) The Involvement of Glutamate System in Schizophrenia
  • 15. 15 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).
  • 16. 16 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).
  • 17. 17 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.
  • 18. 18 (II) The Glutamate Theory vs the Dopamine Theory in Schizophrenia: (Stahl, 2009)
  • 19. 19 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.
  • 20. 20 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.
  • 21. 21 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)
  • 22. 22 The neurophysiological changes in schizophrenia(Stahl, 2009)
  • 23. 23 (1) NMDA-R Hypofunction Hypothesis of Schizophrenia: (Stahl, 2009)
  • 24. 24 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.
  • 25. 25 ROLE OF GLUTAMATE IN THE MESOLIMBIC SYSTEM (Stahl, 2009)
  • 26. 26 ROLE OF GLUTAMATE IN THE MESOCORTICAL SYSTEM (Stahl, 2009)
  • 27. 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
  • 28. 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 ?!!!
  • 29. 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)
  • 30. Role of Post synaptic density (PSD) In Schizophrenia (Iasevoli et al, 2014)
  • 31. 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).
  • 32. 32 (2) The Glutamate Neurodevelopmental Theory of Schizophrenia: The Excessive Synaptic Pruning Theory (Stahl, 2009)
  • 34. 34 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.
  • 35. 35 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.
  • 36. 36 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).
  • 37. 37 (3) Glutmate System and Neurodegenerative Theories of Schizophrenia A. Necrosis theory B. Apoptosis theory
  • 38. 38 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.
  • 39. 39 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
  • 40. 40
  • 41. 41 Glutamate Hypofunctioning Theory vs Glutamate Neurotoxicity Theories of Schizophrenia 1. Two hit theory 2. Three hit theory
  • 42. 42 (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.
  • 43. 43 (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).
  • 45. 45 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
  • 46. 46 (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)
  • 47. 47 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
  • 48. 48 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).
  • 49. 49 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.
  • 51. 51 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
  • 52. 52 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.
  • 53. 53 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)