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The Glutamate Hypothesis of Schizophrenia

Dr Khalid MansourConsultant Psychiatrist

Priory Hospital Cefn CarnauOctober 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.

2. The Glutamate Neurodevelopmental Theory

3. The Glutamate Neurodedegenarative Theory

4. Glutamate Linked Treatments of Schizophrenia

The Glutamate System

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6(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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11NMDA 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) 2. Glutamate linked drugs seem to improve both

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

3. 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.

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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)

33Selemon & 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 theoryB. 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 characterized by 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 theory2. 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

3.NMDA modulators

- mGlu autoreceptors co-agonists- Minocycline

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(1) NMDA Partial Antagonists:To treat excitotoxicity in early and late stage: 1. PCP and Ketamine > highly schizophrenogenic 2. NMDA partial antagonists e.g. Memantine

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

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

4. Anti-free radicals drugs e.g. vitamin E and experimental agents called lazaroids (so-named because they purport to raise neurons from the dead, like the biblical Lazarus) (Stahl, 2009)

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NMDA PARTIAL AGONISTS: GLYCINE CO-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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