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The Glutamate Hypothesis The Glutamate Hypothesis and the Glutamate Linked and the Glutamate Linked

Treatments of Treatments of

SchizophreniaSchizophrenia Dr Khalid MansourDr Khalid Mansour

Locum Consultant PsychiatristLocum Consultant PsychiatristRadbourne UnitRadbourne Unit

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ContentsContents (I) The Glutamate System(I) The Glutamate System

(II) Glutamate System and Schizophrenia(II) Glutamate System and Schizophreniaa- NMDA Receptors Hypofunction Theorya- NMDA Receptors Hypofunction Theory The Glutamate theory vs the Dopamine theory in The Glutamate theory vs the Dopamine theory in

schizophreniaschizophrenia

b- The Glutamate Neurodevelopmental b- The Glutamate Neurodevelopmental Theory Theory

c- The Glutamate Neurodedegenarative c- The Glutamate Neurodedegenarative ModelModel

(III) Glutamate Linked Treatments of (III) Glutamate Linked Treatments of Schizophrenia:Schizophrenia:

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(I)(I) The Glutamate SystemThe Glutamate SystemL-Glutamate:L-Glutamate: ““the king of neurotransmission”the king of neurotransmission”

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The Glutamate System: The Glutamate System: (Moghaddam, 2005)(Moghaddam, 2005)

Glutamate is the major excitatory Glutamate is the major excitatory neurotransmitter in the central nervous neurotransmitter in the central nervous system and the most prevalent one (the system and the most prevalent one (the king of neurotransmission) king of neurotransmission)

Nearly 50% of the neurons in the brain, Nearly 50% of the neurons in the brain, including all neurons that project from the including all neurons that project from the cerebral cortex, are believed to use cerebral cortex, are believed to use glutamate as their neurotransmitter.glutamate as their neurotransmitter.

In mammalians‘ brains, glutamate is In mammalians‘ brains, glutamate is balanced with GABA (main inhibitory balanced with GABA (main inhibitory chemical transmitter): > E/I balance chemical transmitter): > E/I balance (accelerator/break)(accelerator/break)

Both transmitters influence almost every Both transmitters influence almost every other chemical transmitter and brain areas.other chemical transmitter and brain areas.

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Possible therapeutic Possible therapeutic applicationsapplications

(MRC Centre for Synaptic Plasticity(MRC Centre for Synaptic Plasticity 2010)2010)

Multifacet Multifacet ischemia, ischemia,

Epilepsy, Epilepsy, Parkinson's Parkinson's

disease, disease, Alzheimer’s Alzheimer’s

disease, disease, Hyperalgesia, Hyperalgesia,

Diabetes, Diabetes, Multiple Multiple

Sclerosis,Sclerosis,Schizophrenia, Schizophrenia, Anxiety, Anxiety, Depression, Depression, etc. etc.

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Glutamate Receptors: Glutamate Receptors: (MRC Centre for Synaptic Plasticity(MRC Centre for Synaptic Plasticity 2010)2010)

Glutamate acts via two classes of Glutamate acts via two classes of receptors which spread in both receptors which spread in both neurones and glial cells:neurones and glial cells:Ligand gated ion channels (Ligand gated ion channels (Ionotropic Ionotropic

receptorsreceptors):):Four groups (Four groups (AMPA, NMDA, Kinate AMPA, NMDA, Kinate

andand Delta Delta receptors). receptors).G-protein coupled (G-protein coupled (MetabotropicMetabotropic

receptorsreceptors).).They are further broken down into They are further broken down into

three groups and eight subgroups: three groups and eight subgroups: (mGlu1-mGlu8).(mGlu1-mGlu8).

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Glutamate receptors Glutamate receptors

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Metabotropic Glutamate Metabotropic Glutamate ReceptorsReceptors

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(II) Glutamate (II) Glutamate system and system and

schizophreniaschizophrenia(1)(1) NMDA Receptors Hypofunction NMDA Receptors Hypofunction

Hypothesis of Schizophrenia Hypothesis of Schizophrenia - - (The Glutamate (The Glutamate theory vs the Dopamine theory in schizophrenia)theory vs the Dopamine theory in schizophrenia)

(2)(2) The Glutamate Excitotoxicity as part of The Glutamate Excitotoxicity as part of the Neurodevelopmental Theory of the Neurodevelopmental Theory of SchizophreniaSchizophrenia

(3)(3) The Glutamate Excitotoxicity as part of The Glutamate Excitotoxicity as part of the Neurodedegenarative Model of the Neurodedegenarative Model of SchizophreniaSchizophrenia

(1) NMDA Receptors (1) NMDA Receptors Hypofunction Hypofunction Hypothesis of Hypothesis of Schizophrenia:Schizophrenia:The Glutamate theory vs. the The Glutamate theory vs. the

Dopamine theory in schizophreniaDopamine theory in schizophrenia

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Glutamate system and Glutamate system and schizophreniaschizophrenia (Moghaddam, 2005)(Moghaddam, 2005)

The idea of a glutamatergic The idea of a glutamatergic abnormality in schizophrenia was abnormality in schizophrenia was first proposed by Kim and first proposed by Kim and colleagues in 1980 (Kim et al., colleagues in 1980 (Kim et al., 1980) based on their findings of 1980) based on their findings of low cerebrospinal fluid (CSF) low cerebrospinal fluid (CSF) glutamate levels in patients with glutamate levels in patients with schizophrenia. schizophrenia.

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Glutamate system and Glutamate system and schizophreniaschizophrenia (Moghaddam, 2005)(Moghaddam, 2005)

Studies about Antiglutamatergic substances:Studies about Antiglutamatergic substances: Phencyclidine (PCP) or ketamine produces Phencyclidine (PCP) or ketamine produces

"schizophrenia-like" symptoms in healthy "schizophrenia-like" symptoms in healthy individuals and profoundly exacerbates pre-individuals and profoundly exacerbates pre-existing symptoms in patients with schizophrenia existing symptoms in patients with schizophrenia (Javitt et al., 1991; Krystal et al., 1994; Lahti et (Javitt et al., 1991; Krystal et al., 1994; Lahti et al., 1995). al., 1995).

The range of symptoms produced by these The range of symptoms produced by these agents resembles agents resembles

positive symptoms of schizophrenia (delusion and positive symptoms of schizophrenia (delusion and hallucination), hallucination),

negative symptoms (avolition, apathy, and blunted negative symptoms (avolition, apathy, and blunted affect), affect),

cognitive (deficits in attention, memory, and abstract cognitive (deficits in attention, memory, and abstract reasoning) reasoning)

disruptions in smooth-pursuit eye movements disruptions in smooth-pursuit eye movements disruptions in prepulse inhibition of startle. disruptions in prepulse inhibition of startle.

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Glutamate system and Glutamate system and schizophreniaschizophrenia (Moghaddam, 2005)(Moghaddam, 2005)

Genetic studies:Genetic studies: The majority of the genes that have The majority of the genes that have

recently been associated with an increased recently been associated with an increased risk for schizophrenia can influence risk for schizophrenia can influence function linked to glutamate receptors function linked to glutamate receptors (Harrison et al., 2003; Moghaddam, 2003). (Harrison et al., 2003; Moghaddam, 2003).

Postmortem receptors studies:Postmortem receptors studies: Postmortem studies show changes in Postmortem studies show changes in

glutamate receptor binding, transcription, glutamate receptor binding, transcription, and subunit protein expression in the and subunit protein expression in the prefrontal cortex, thalamus, and prefrontal cortex, thalamus, and hippocampus of subjects with hippocampus of subjects with schizophrenia (Clinton and Meador-schizophrenia (Clinton and Meador-Woodruff, 2004).Woodruff, 2004).

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Glutamate system and Glutamate system and schizophreniaschizophrenia (Moghaddam, 2005)(Moghaddam, 2005)

Postmortem enzymes studies:Postmortem enzymes studies: Levels of amino acids N-acethylaspartate Levels of amino acids N-acethylaspartate

(NAA) and N-acethylaspartylglutamate (NAA) and N-acethylaspartylglutamate (NAAG), and the activity of the enzyme that (NAAG), and the activity of the enzyme that cleaves NAA to NAAG and glutamate are cleaves NAA to NAAG and glutamate are altered in the CSF and postmortem tissue altered in the CSF and postmortem tissue from individuals with schizophrenia (Tsai et from individuals with schizophrenia (Tsai et al., 1995). al., 1995).

Brain imaging studies:Brain imaging studies: Recent imaging studies using a novel SPECT Recent imaging studies using a novel SPECT

tracer for the NMDA receptor (123I)CNS-tracer for the NMDA receptor (123I)CNS-1261 (Pilowsky et al., 2005) have reported 1261 (Pilowsky et al., 2005) have reported reduced NMDA receptor binding in the reduced NMDA receptor binding in the hippocampus of medication-free patients. hippocampus of medication-free patients.

The Glutamate theory The Glutamate theory vs vs

the Dopamine theory the Dopamine theory in in

schizophreniaschizophrenia

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Dopamine Theory: the golden Dopamine Theory: the golden triadtriad

1.1. Drugs that increase dopamine, such Drugs that increase dopamine, such as amphetamine and cocaine, can as amphetamine and cocaine, can cause psychosis.cause psychosis.

2. Antidopaminergic drugs can  drugs can  improve psychosis.improve psychosis.

3.3. Identified mechanism: overactivity Identified mechanism: overactivity in the mesolimbic dopamine in the mesolimbic dopamine pathway could be the mediator of pathway could be the mediator of positive symptoms of schizophrenia positive symptoms of schizophrenia such as delusions and such as delusions and hallucinations.hallucinations.

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Dopamine Theory: problemsDopamine Theory: problems

It explains only part of schizophrenia It explains only part of schizophrenia (positive symptoms not negative (positive symptoms not negative symptoms)symptoms)

Anti-dopamenergic drugs usually Anti-dopamenergic drugs usually make negative symptoms worse in patientsmake negative symptoms worse in patientsinduce negative symptoms in healthy induce negative symptoms in healthy

people.people.Atypical antipsychotic drugs e.g. Atypical antipsychotic drugs e.g.

Clozapine (with weaker anti-Clozapine (with weaker anti-dopaminergic activity) are better anti-dopaminergic activity) are better anti-schizophrenic drugs. schizophrenic drugs.

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Dopamine Theory: problemsDopamine Theory: problems

Under activity in  the meso-cortical Under activity in  the meso-cortical dopamine pathway is hypothesized dopamine pathway is hypothesized to be the mediator of negative to be the mediator of negative symptoms of schizophrenia: this symptoms of schizophrenia: this indicates that reduced dopamine indicates that reduced dopamine activity is the problem rather than activity is the problem rather than dopamine overactivity.dopamine overactivity.

DA theory is a “psychosis theory” DA theory is a “psychosis theory” more than it is a “schizophrenia more than it is a “schizophrenia theory”.theory”.

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Key DA PathwaysKey DA Pathways

(a) The nigrostriatal pathway. (b) The mesolimbic pathway. (c) The mesocortical pathway (dorsolateral prefrontal (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 pathwaycortex & ventromedial cortex). (d) The tuberoinfundibular pathway. (e) The thalamic DA pathway

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The DA Hypothesis of Schizophrenia: Positive SymptomsThe DA Hypothesis of Schizophrenia: Positive Symptoms

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The DA Hypothesis of Schizophrenia: Negative, Cognitive, and Affective The DA Hypothesis of Schizophrenia: Negative, Cognitive, and Affective SymptomsSymptoms

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Role of Glutamate in the Mesolimbic SystemRole of Glutamate in the Mesolimbic System

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Role of Glutamate in the Mesocortical SystemRole of Glutamate in the Mesocortical System

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Glutamate Hypofunctioning Theory: golden triad

1.1. Antiglutamatergic drugs e.g. PCP and Antiglutamatergic drugs e.g. PCP and Ketamine > NMDA receptors Ketamine > NMDA receptors hypofunctional >hypofunctional >

positive symptoms such as delusions and positive symptoms such as delusions and hallucinationshallucinations

Affective, negative and cognitive symptoms Affective, negative and cognitive symptoms Physiological symptoms of schizophreniaPhysiological symptoms of schizophrenia

2.2. Glutamate linked drugs seems, so far, to Glutamate linked drugs seems, so far, to improve both positive and negative improve both positive and negative symptoms of schizophreniasymptoms of schizophrenia

3.3. Neurophysiological studies also suggest Neurophysiological studies also suggest that hypofunction of NMDA receptors could that hypofunction of NMDA receptors could better explain the negative, cognitive and better explain the negative, cognitive and affective symptoms of schizophrenia.affective symptoms of schizophrenia.

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(2) The Glutamate (2) The Glutamate Excitotoxicity as part of the Excitotoxicity as part of the Neurodevelopmental Theory Neurodevelopmental Theory

of Schizophreniaof Schizophrenia

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Neurodevelopmental Theory of Neurodevelopmental Theory of

SchizophreniaSchizophrenia (Fatemi & Folsom, 2009)(Fatemi & Folsom, 2009) Schizophrenia could be the result of an

early brain insult, which affects brain development leading to abnormalities in the mature brain (Murray et al, 1992).

The theory has been postulated since Kraeplin in the early 20th century.

The cause of the brain lesion is postulated to be either of abnormal genes, which impair brain development, or from some foetal or neonatal adversity. 

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Neurodevelopmental Theory of Neurodevelopmental Theory of

Schizophrenia: EvidenceSchizophrenia: Evidence (Fatemi & (Fatemi &

Folsom, 2009)Folsom, 2009) Congenital Abnormalities: e.g. agenesis of

corpus callosum, stenosis of sylvian aqueduct, cerebral hamartomas, low-set ears, epicanthal eye folds, etc.

Environmental Factors: e.g. obstetric and perinatal complications, periventicular hemorrhages, hypoxia, and ischemic injuries and prenatal viral infections.

Biological markersBiological markers: e.g. changes in the : e.g. changes in the proteins that are involved in early migration proteins that are involved in early migration of neurons and glia, cell proliferation, axonal of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and outgrowth, synaptogenesis, and apoptosisapoptosis

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Neurodevelopmental Theory of Neurodevelopmental Theory of

Schizophrenia: EvidenceSchizophrenia: Evidence (Fatemi & (Fatemi & Folsom, 2009)Folsom, 2009)

Genetics Genetics studies: e.g. various gene families, studies: e.g. various gene families, involved in schizophrenia, involved in signal involved in schizophrenia, involved in signal transduction, cell growth and migration, transduction, cell growth and migration, myelination, regulation of presynaptic myelination, regulation of presynaptic membrane function, and GABAergic membrane function, and GABAergic function. function.

Brain Pathology:Brain Pathology: e.g. cortical atrophy, e.g. cortical atrophy, ventricular enlargement, reduced volume of ventricular enlargement, reduced volume of various brain parts, abnormal laminar various brain parts, abnormal laminar organization and orientation of neurons, organization and orientation of neurons, decreased cellularity and cerebellar atrophy decreased cellularity and cerebellar atrophy

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Neurodevelopmental Theory Neurodevelopmental Theory of Schizophrenia of Schizophrenia (Gupta & Kulhara, 2010)(Gupta & Kulhara, 2010)

During adolescence, brain changes normally During adolescence, brain changes normally include: include: Decrease in delta sleepDecrease in delta sleepDecrease in membrane synthesis Decrease in membrane synthesis Decreased volume of cortical gray matterDecreased volume of cortical gray matterDecreased prefrontal metabolismDecreased prefrontal metabolism

In schizophrenia, there are more pronounced In schizophrenia, there are more pronounced decrements in the same parameters.decrements in the same parameters.

Feinberg (1983):Feinberg (1983): t this supports the possibility his supports the possibility of an exaggeration of the normal process of of an exaggeration of the normal process of synaptic synaptic pruningpruning that occurs in that occurs in schizophrenia during adolescence .schizophrenia during adolescence .

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Neurodevelopmental Neurodevelopmental Theory of Schizophrenia: Theory of Schizophrenia:

Models Models ((Corroon, 2005))The early neurodevelopmental The early neurodevelopmental

model:model: fixed lesion from early life fixed lesion from early life interacts with normal neurodevelopment interacts with normal neurodevelopment occurring later, lying dormant until the occurring later, lying dormant until the brain matures sufficiently to call into brain matures sufficiently to call into operation the damaged systems (Murray operation the damaged systems (Murray & Lewis, 1987).& Lewis, 1987).

The late neurodevelopmental model:The late neurodevelopmental model: schizophrenia may result from an schizophrenia may result from an abnormality in peri-adolescent synaptic abnormality in peri-adolescent synaptic pruning (pruning (Feinberg, 1983Feinberg, 1983).).

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Neurodevelopmental Theory of Schizophrenia: Neurodevelopmental Theory of Schizophrenia:

“2-hit” model“2-hit” model (Fatemi & Folsom, 2009)(Fatemi & Folsom, 2009) Keshavan and Hogarty (1999):Keshavan and Hogarty (1999):

maldevelopment in schizophrenia takes maldevelopment in schizophrenia takes place during 2 critical time points (early place during 2 critical time points (early brain development and adolescence): brain development and adolescence): Early developmental insults may lead to Early developmental insults may lead to

dysfunction of specific neural networks that dysfunction of specific neural networks that would account for premorbid signswould account for premorbid signs

At adolescence, excessive synaptic pruning At adolescence, excessive synaptic pruning and loss of plasticity may account for the and loss of plasticity may account for the emergence of symptoms.emergence of symptoms.

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Glutmate and Glutmate and Neurodevelopmental Theory of Neurodevelopmental Theory of

SchizophreniaSchizophrenia

NMDA receptors a critical component NMDA receptors a critical component of developmental processes during of developmental processes during adolescence (Moghaddam, 2005). adolescence (Moghaddam, 2005). This includes: This includes: development of neural pathwaysdevelopment of neural pathwaysNeural migration, Neural migration, Neural survival, Neural survival, Neural plasticity Neural plasticity Neural pruning of cortical connectionsNeural pruning of cortical connections

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Glutmate and Glutmate and Neurodevelopmental Theory of Neurodevelopmental Theory of

SchizophreniaSchizophreniaStahl (2009): suggests that Stahl (2009): suggests that

Glutamate excitotoxicity first Glutamate excitotoxicity first facilitates the neurodevelopmental facilitates the neurodevelopmental disorder in adolescence.disorder in adolescence.

Later, this results in a chronic state Later, this results in a chronic state of Glutamate hypofunctioning which of Glutamate hypofunctioning which maintains the schizophrenic maintains the schizophrenic pathology in later stages. pathology in later stages.

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(3) The Glutamate (3) The Glutamate Excitotoxicity as part of the Excitotoxicity as part of the Neurodedegenarative Model Neurodedegenarative Model

of Schizophreniaof Schizophrenia

Glutamate and Glutamate and Neurodegenerative Model of Neurodegenerative Model of

Schizophrenia Schizophrenia (Woods, 1998)(Woods, 1998) Kraeplin and others believed that Schizophrenia is Kraeplin and others believed that Schizophrenia is

caused by a form of progressive neuronal caused by a form of progressive neuronal degeneration characterizeddegeneration characterized by earlier onset than that by earlier onset than that seen with previously described entities,seen with previously described entities, such as such as Huntington's disease or Alzheimer's disease > Huntington's disease or Alzheimer's disease > Dementia praecox Dementia praecox

However, the However, the neurodegenerativeneurodegenerative theory theory was opposed was opposed by the neurodevelopmental theory: by the neurodevelopmental theory: most of the brain most of the brain pathology in schizophrenia starts in early adulthood, pathology in schizophrenia starts in early adulthood, no evidence of necrosis and that there is no no evidence of necrosis and that there is no neurochemical explanation for neurodegeneration.neurochemical explanation for neurodegeneration.

Theory was later supported by the discoveries about Theory was later supported by the discoveries about apoptosisapoptosis and and glutamate glutamate system. system.

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Glutamate and Glutamate and Neurodegenerative Model of Neurodegenerative Model of

SchizophreniaSchizophrenia (Glantz et al, 2006; Jarskog et al, 2005)(Glantz et al, 2006; Jarskog et al, 2005)

Above mentioned neurostructural changes in Above mentioned neurostructural changes in schizophrenia have led to the hypothesis that schizophrenia have led to the hypothesis that apoptosisapoptosis (programmed cell death) may contribute to (programmed cell death) may contribute to the pathophysiology of schizophrenia. Such changes the pathophysiology of schizophrenia. Such changes include:include: Reduced neuropils (Reduced neuropils (region between neuronal cell region between neuronal cell

bodies in the gray matterbodies in the gray matter) and reductions of ) and reductions of neurons. neurons.

Nneuroimaging data > progressive loss of cortical Nneuroimaging data > progressive loss of cortical grey matter in schizophrenia . grey matter in schizophrenia .

Postmortem studies: markers of apoptosis and levels Postmortem studies: markers of apoptosis and levels of apoptotic proteins indicate > increased apoptotic of apoptotic proteins indicate > increased apoptotic vulnerability. vulnerability.

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Glutamate and Glutamate and Neurodegenerative Model of Neurodegenerative Model of

SchizophreniaSchizophrenia Again glutamate is the main factor Again glutamate is the main factor

involved in involved in apoptosisapoptosis (Stahl, 2009): (Stahl, 2009): High concentrations of glutamate accumulate High concentrations of glutamate accumulate

in the brain are thought to be involved in the in the brain are thought to be involved in the aetiology of a number of neurodegenerative aetiology of a number of neurodegenerative disorders including Alzheimer's disease (Coyle disorders including Alzheimer's disease (Coyle & Puttfarcken, 1993; Lipton & Rosenberg, & Puttfarcken, 1993; Lipton & Rosenberg, 1994;). 1994;).

A number of invitro studies > at high A number of invitro studies > at high concentrations, glutamate is a potent concentrations, glutamate is a potent neurotoxin capable of destroying neurons by neurotoxin capable of destroying neurons by apoptosis (Behl et al. 1995; Zhang & Bhavnani, apoptosis (Behl et al. 1995; Zhang & Bhavnani, 2003).2003).

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Conclusion of Glutmate role in Conclusion of Glutmate role in SchizophreniaSchizophrenia

Both glutamate Both glutamate hypohypoactivity as well as activity as well as hyperhyperactivity contribute to the pathology of activity contribute to the pathology of schizophrenia (Stahl, 2009). schizophrenia (Stahl, 2009).

Gupta & Kulhara (2010) suggested that:Gupta & Kulhara (2010) suggested that:Schizophrenia cannot be explained by a Schizophrenia cannot be explained by a

single process of development or single process of development or degeneration. degeneration.

Research evidence exists for Research evidence exists for degeneration as well as developmental degeneration as well as developmental disorders. disorders.

The glutamatergic hypothesis bridges the The glutamatergic hypothesis bridges the gap between development and gap between development and neurodegeneration in schizophrenia > neurodegeneration in schizophrenia > "three hit hypothesis""three hit hypothesis" (Keshavan, 1999). (Keshavan, 1999).

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Clinical and pathological stages Clinical and pathological stages of schizophrenia of schizophrenia (Gupta & Kulhara, 2010)(Gupta & Kulhara, 2010)

                                                                                                                                                                                                                                                                                                                                                                                                                                                              

  

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Glutamate Linked Glutamate Linked Treatments of Treatments of Schizophrenia:Schizophrenia:

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Glutamate Linked Treatments of Glutamate Linked Treatments of Schizophrenia: Schizophrenia:

Three classes of medications: Three classes of medications: 1.1. NMDA partial antagonists (early stage NMDA partial antagonists (early stage

schizophrenia)schizophrenia)

2.2. NMDA partial agonists (later stage NMDA partial agonists (later stage schizophrenia):schizophrenia):

- Glycine co-agonistsGlycine co-agonists- Glycine transporters inhibitorsGlycine transporters inhibitors

3.3. NMDA modulatorsNMDA modulators- mGlu autoreceptors co-agonistsmGlu autoreceptors co-agonists- MinocyclineMinocycline

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(1) NMDA Partial (1) NMDA Partial AntagonistsAntagonists:: (Stahl, 2009) (Stahl, 2009)

To treat excitotoxicity in early stageTo treat excitotoxicity in early stage: : PCP and Ketamine: highly PCP and Ketamine: highly schizophrenogenic NMDA partial antagonists e.g. memantine NMDA partial antagonists e.g. memantine

(already used in Alzheimer)(already used in Alzheimer) Drugs which block presynaptic release of Drugs which block presynaptic release of

glutamate e.g. Lamotrigine, gabapentin and glutamate e.g. Lamotrigine, gabapentin and pregabalin.pregabalin.

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

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NMDA Partial Agonists:NMDA Partial Agonists: glycine co-agonistsglycine co-agonists

To treat glutamate hypofunctioning in To treat glutamate hypofunctioning in later stages of schiz:later stages of schiz:

Chaves et al (2009): the main Chaves et al (2009): the main strategy used in the last two strategy used in the last two decades has relied on agonists at decades has relied on agonists at the allosteric glycine receptor site the allosteric glycine receptor site of the NMDA complex (glycine co-of the NMDA complex (glycine co-agonists) as a way to avoid causing agonists) as a way to avoid causing glutamate neurotoxicity.glutamate neurotoxicity.

Two ways to this:Two ways to this:

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Glycine Co-agonists as Partial Glycine Co-agonists as Partial NMDA AgonistsNMDA Agonists:: (Chaves et al, 2009) (Chaves et al, 2009)

(Stahl, 2009)(Stahl, 2009)

(a)(a) Glycine agonists to activate glycine co-Glycine agonists to activate glycine co-agonist site on the NMDA receptos as agonist site on the NMDA receptos as indirect way to potentiate the glutamte indirect way to potentiate the glutamte effect effect

e.g. e.g. glycine, d-serine, d-alanine and d-cycloserine.glycine, d-serine, d-alanine and d-cycloserine. Provisional studies are promising. Provisional studies are promising. Research is still going on, using stronger agonistsResearch is still going on, using stronger agonists

(b) (b) Glycine transporters inhibitors (GlyT1 Glycine transporters inhibitors (GlyT1 inhibitirs): inhibitirs): e.g. e.g. sarcosinesarcosine > promising > promising remedy for negative symptoms of remedy for negative symptoms of schizophreniaschizophrenia

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NMDA ModulatorsNMDA ModulatorsmGlu autoreceptors co-agonistsmGlu autoreceptors co-agonists

Wieronska and Pilc (2009):Wieronska and Pilc (2009): mGlu mGlu receptors as the ideal target for receptors as the ideal target for medication especially if using the mGlu medication especially if using the mGlu receptors allosteric binding sites (co-receptors allosteric binding sites (co-agonists) e.g. methionine amide.agonists) e.g. methionine amide.

Mechanisms of action are not quite clearMechanisms of action are not quite clear mGluR2/3 are mainly autoreceptors that mGluR2/3 are mainly autoreceptors that

prevent glutamate release. prevent glutamate release. The final result is enhancing glutamate The final result is enhancing glutamate

activity (?). activity (?).

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MetabotropicMetabotropic glutamate glutamate receptorsreceptors

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NMDA Modulators: NMDA Modulators: mGlu2/3 autoreceptors co-mGlu2/3 autoreceptors co-

agonistsagonists They reverse the effects of PCP and They reverse the effects of PCP and Ketamine in animals (Stahl, 2009)Ketamine in animals (Stahl, 2009)

Some studies > methionine amide: Some studies > methionine amide: effective against + ve and - ve effective against + ve and - ve symptoms of schizophrenia (Moghaddam, symptoms of schizophrenia (Moghaddam, 2005).2005).

A RCT > after four weeks of treatment, A RCT > after four weeks of treatment, an agonist for the mGluR2/3 (LY404039 ) an agonist for the mGluR2/3 (LY404039 ) has similar efficacy as Olanzapine in has similar efficacy as Olanzapine in ameliorating positive and negative ameliorating positive and negative symptoms of schizophrenia (Patil et al., symptoms of schizophrenia (Patil et al., 2007). 2007).

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NMDA Modulators:NMDA Modulators: MinocyclineMinocycline

(Chaves et al, 2009)(Chaves et al, 2009) second-generation tetracycline with a second-generation tetracycline with a

broad spectrum of antimicrobial activities broad spectrum of antimicrobial activities and anti-inflammatory properties and anti-inflammatory properties

latest studies suggest that it is related to latest studies suggest that it is related to the glutamatergic system: minocycline the glutamatergic system: minocycline reversed several NMDA antagonist effects reversed several NMDA antagonist effects in animal studies and showed good results in animal studies and showed good results in the treatment of patients with in the treatment of patients with schizophreniaschizophrenia

Has neuroprotective effects in several Has neuroprotective effects in several animal and human models of neurological animal and human models of neurological diseases, including Parkinson's disease, diseases, including Parkinson's disease, amyotrophic lateral sclerosis, Huntington's amyotrophic lateral sclerosis, Huntington's disease, and ischemia disease, and ischemia

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CommentsComments Glutamate hypothesis is a welcome addition but it is not well Glutamate hypothesis is a welcome addition but it is not well

developed yet, many issues need clarification e.g. developed yet, many issues need clarification e.g. Interactions between glutamte system, glycine system, monoamines Interactions between glutamte system, glycine system, monoamines

and other systems. and other systems. Usage of glutamte kinked drugs in treatment of schizophrenia and Usage of glutamte kinked drugs in treatment of schizophrenia and

possible effects on depression, anxiety, epilepsy, etcpossible effects on depression, anxiety, epilepsy, etc Glutamte excitotoxicity and NMDA hypofunctioning in schizophrenia is Glutamte excitotoxicity and NMDA hypofunctioning in schizophrenia is

not clear not clear Why mGlu2/3R agonists can enhance glutamate activities despite of Why mGlu2/3R agonists can enhance glutamate activities despite of

the fact that they should be reducing the release of glutamate?the fact that they should be reducing the release of glutamate? Why Why Glutamate linked drugs are only used as augmentation with atypical Glutamate linked drugs are only used as augmentation with atypical

antipsychotic drugs?antipsychotic drugs? We need to avoid the dopamine mistake:We need to avoid the dopamine mistake:

Could it be over simplistic to attribute a major illness to the mere Could it be over simplistic to attribute a major illness to the mere quantitative increase or decrease of one chemical transmitter?quantitative increase or decrease of one chemical transmitter?

Could it be over simplistic to assume that schizophrenia is a one illness Could it be over simplistic to assume that schizophrenia is a one illness with a one neurochemical pathology.with a one neurochemical pathology.

Is possible that glutamate theory is a theory of something else e.g. Is possible that glutamate theory is a theory of something else e.g. neuronal excitability (like it is assumed to be in epilepsy and anxiety) neuronal excitability (like it is assumed to be in epilepsy and anxiety) rather than schizophrenia theory. This would be similar to the rather than schizophrenia theory. This would be similar to the argument that dopamine theory is a theory of psychosis not of argument that dopamine theory is a theory of psychosis not of schizophrenia? schizophrenia?

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Clinical QuestionsClinical Questions

Side effects and secondary effects of Side effects and secondary effects of already present Antiglutamatergic already present Antiglutamatergic drugs on mental illnesses e.g. drugs on mental illnesses e.g. Drugs which block presynaptic release of Drugs which block presynaptic release of

glutamate e.g. Lamotrigine, gabapentin glutamate e.g. Lamotrigine, gabapentin and pregabalin, can they cause and pregabalin, can they cause deterioration of schizophrenia?deterioration of schizophrenia?

Can GABA-ergic drugs like sodium Can GABA-ergic drugs like sodium valproate be a better choice in valproate be a better choice in schizophrenia? schizophrenia?

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Thank you Thank you