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Locum Consultant Psychiatrist

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1 Locum Consultant Psychiatrist
The Glutamate Hypothesis and the Glutamate Linked Treatments of Schizophrenia Dr Khalid Mansour Locum Consultant Psychiatrist Radbourne Unit

2 Contents (I) The Glutamate System
(II) Glutamate System and Schizophrenia a- NMDA Receptors Hypofunction Theory The Glutamate theory vs the Dopamine theory in schizophrenia b- The Glutamate Neurodevelopmental Theory c- The Glutamate Neurodedegenarative Model (III) Glutamate Linked Treatments of Schizophrenia:

3 The Glutamate System L-Glutamate: “the king of neurotransmission”

4 The Glutamate System: (Moghaddam, 2005)
Glutamate is the major excitatory neurotransmitter in the central nervous system and the most prevalent one (the king of neurotransmission) Nearly 50% of the neurons in the brain, including all neurons that project from the cerebral cortex, are believed to use glutamate as their neurotransmitter. In mammalians‘ brains, glutamate is balanced with GABA (main inhibitory chemical transmitter): > E/I balance (accelerator/break) Both transmitters influence almost every other chemical transmitter and brain areas.

5 Possible therapeutic applications (MRC Centre for Synaptic Plasticity 2010)
Diabetes, Multiple Sclerosis, Schizophrenia, Anxiety, Depression, etc. Multifacet ischemia, Epilepsy, Parkinson's disease, Alzheimer’s disease, Hyperalgesia,

6 Glutamate Receptors: (MRC Centre for Synaptic Plasticity 2010)
Glutamate acts via two classes of receptors which spread in both neurones and glial cells: Ligand gated ion channels (Ionotropic receptors): Four groups (AMPA, NMDA, Kinate and Delta receptors). G-protein coupled (Metabotropic receptors). They are further broken down into three groups and eight subgroups: (mGlu1-mGlu8).

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9 Glutamate receptors

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11 Metabotropic Glutamate Receptors

12 (II) Glutamate system and schizophrenia
NMDA Receptors Hypofunction Hypothesis of Schizophrenia (The Glutamate theory vs the Dopamine theory in schizophrenia) The Glutamate Excitotoxicity as part of the Neurodevelopmental Theory of Schizophrenia The Glutamate Excitotoxicity as part of the Neurodedegenarative Model of Schizophrenia

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

14 Glutamate system and schizophrenia (Moghaddam, 2005)
The idea of a glutamatergic abnormality in schizophrenia was first proposed by Kim and colleagues in 1980 (Kim et al., 1980) based on their findings of low cerebrospinal fluid (CSF) glutamate levels in patients with schizophrenia.

15 Glutamate system and schizophrenia (Moghaddam, 2005)
Studies about Antiglutamatergic substances: Phencyclidine (PCP) or ketamine produces "schizophrenia-like" symptoms in healthy individuals and profoundly exacerbates pre-existing symptoms in patients with schizophrenia (Javitt et al., 1991; Krystal et al., 1994; Lahti et al., 1995). The range of symptoms produced by these agents resembles positive symptoms of schizophrenia (delusion and hallucination), negative symptoms (avolition, apathy, and blunted affect), cognitive (deficits in attention, memory, and abstract reasoning) disruptions in smooth-pursuit eye movements disruptions in prepulse inhibition of startle.

16 Glutamate system and schizophrenia (Moghaddam, 2005)
Genetic studies: The majority of the genes that have recently been associated with an increased risk for schizophrenia can influence function linked to glutamate receptors (Harrison et al., 2003; Moghaddam, 2003). Postmortem receptors studies: Postmortem studies show changes in glutamate receptor binding, transcription, and subunit protein expression in the prefrontal cortex, thalamus, and hippocampus of subjects with schizophrenia (Clinton and Meador-Woodruff, 2004).

17 Glutamate system and schizophrenia (Moghaddam, 2005)
Postmortem enzymes studies: Levels of amino acids N-acethylaspartate (NAA) and N-acethylaspartylglutamate (NAAG), and the activity of the enzyme that cleaves NAA to NAAG and glutamate are altered in the CSF and postmortem tissue from individuals with schizophrenia (Tsai et al., 1995). Brain imaging studies: Recent imaging studies using a novel 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 The Glutamate theory vs the Dopamine theory in schizophrenia

19 Dopamine Theory: the golden triad
Drugs that increase dopamine, such as amphetamine and cocaine, can cause psychosis. Antidopaminergic drugs can  improve psychosis. Identified mechanism: overactivity in the mesolimbic dopamine pathway could be the mediator of positive symptoms of schizophrenia such as delusions and hallucinations.

20 Dopamine Theory: problems
It explains only part of schizophrenia (positive symptoms not negative symptoms) Anti-dopamenergic drugs usually make negative symptoms worse in patients induce negative symptoms in healthy people. Atypical antipsychotic drugs e.g. Clozapine (with weaker anti-dopaminergic activity) are better anti-schizophrenic drugs.

21 Dopamine Theory: problems
Under activity in  the meso-cortical dopamine pathway is hypothesized to be the mediator of negative symptoms of schizophrenia: this indicates that reduced dopamine activity is the problem rather than dopamine overactivity. DA theory is a “psychosis theory” more than it is a “schizophrenia theory”.

22 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

23 The DA Hypothesis of Schizophrenia: Positive Symptoms

24 The DA Hypothesis of Schizophrenia: Negative, Cognitive, and Affective Symptoms

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26 Role of Glutamate in the Mesolimbic System

27 Role of Glutamate in the Mesocortical System

28 Glutamate Hypofunctioning Theory: golden triad
Antiglutamatergic drugs e.g. PCP and Ketamine > NMDA receptors hypofunctional > positive symptoms such as delusions and hallucinations Affective, negative and cognitive symptoms Physiological symptoms of schizophrenia Glutamate linked drugs seems, so far, to improve both positive and negative symptoms of schizophrenia Neurophysiological studies also suggest that hypofunction of NMDA receptors could better explain the negative, cognitive and affective symptoms of schizophrenia.

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

30 Neurodevelopmental Theory of Schizophrenia (Fatemi & Folsom, 2009)
Schizophrenia could be the result of an early brain insult, which affects brain development leading to abnormalities in the mature  brain (Murray et al, 1992). The theory has been postulated since Kraeplin in the early 20th century. The cause of the brain lesion is postulated to be either of abnormal genes, which impair brain development, or from some foetal or neonatal adversity. 

31 Neurodevelopmental Theory of Schizophrenia: Evidence (Fatemi & Folsom, 2009)
Congenital Abnormalities: e.g. agenesis of corpus callosum, stenosis of sylvian aqueduct, cerebral hamartomas, low-set ears, epicanthal eye folds, etc. Environmental Factors: e.g. obstetric and perinatal complications, periventicular hemorrhages, hypoxia, and ischemic injuries and prenatal viral infections. Biological markers: e.g. changes in the proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis

32 Neurodevelopmental Theory of Schizophrenia: Evidence (Fatemi & Folsom, 2009)
Genetics studies: e.g. various gene families, involved in schizophrenia, involved in signal transduction, cell growth and migration, myelination, regulation of presynaptic membrane function, and GABAergic function. Brain Pathology: e.g. cortical atrophy, ventricular enlargement, reduced volume of various brain parts, abnormal laminar organization and orientation of neurons, decreased cellularity and cerebellar atrophy

33 Neurodevelopmental Theory of Schizophrenia (Gupta & Kulhara, 2010)
During adolescence, brain changes normally include: Decrease in delta sleep Decrease in membrane synthesis Decreased volume of cortical gray matter Decreased prefrontal metabolism In schizophrenia, there are more pronounced decrements in the same parameters. Feinberg (1983): this supports the possibility of an exaggeration of the normal process of synaptic pruning that occurs in schizophrenia during adolescence .

34 Neurodevelopmental Theory of Schizophrenia: Models (Corroon, 2005)
The early neurodevelopmental model: fixed lesion from early life interacts with normal neurodevelopment occurring later, lying dormant until the brain matures sufficiently to call into operation the damaged systems (Murray & Lewis, 1987). The late neurodevelopmental model: schizophrenia may result from an abnormality in peri-adolescent synaptic pruning (Feinberg, 1983).

35 Neurodevelopmental Theory of Schizophrenia: “2-hit” model (Fatemi & Folsom, 2009)
Keshavan and Hogarty (1999): maldevelopment in schizophrenia takes place during 2 critical time points (early brain development and adolescence): Early developmental insults may lead to dysfunction of specific neural networks that would account for premorbid signs At adolescence, excessive synaptic pruning and loss of plasticity may account for the emergence of symptoms.

36 Glutmate and Neurodevelopmental Theory of Schizophrenia
NMDA receptors a critical component of developmental processes during adolescence (Moghaddam, 2005). This includes: development of neural pathways Neural migration, Neural survival, Neural plasticity Neural pruning of cortical connections

37 Glutmate and Neurodevelopmental Theory of Schizophrenia
Stahl (2009): suggests that Glutamate excitotoxicity first facilitates the neurodevelopmental disorder in adolescence. Later, this results in a chronic state of Glutamate hypofunctioning which maintains the schizophrenic pathology in later stages.

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

39 Glutamate and Neurodegenerative Model of Schizophrenia (Woods, 1998)
Kraeplin and others believed that Schizophrenia is caused by a form of progressive neuronal degeneration characterized by earlier onset than that seen with previously described entities, such as Huntington's disease or Alzheimer's disease > Dementia praecox However, the neurodegenerative theory was opposed by the neurodevelopmental theory: most of the brain pathology in schizophrenia starts in early adulthood, no evidence of necrosis and that there is no neurochemical explanation for neurodegeneration. Theory was later supported by the discoveries about apoptosis and glutamate system.

40 Glutamate and Neurodegenerative Model of Schizophrenia (Glantz et al, 2006; Jarskog et al, 2005)
Above mentioned neurostructural changes in schizophrenia have led to the hypothesis that apoptosis (programmed cell death) may contribute to the pathophysiology of schizophrenia. Such changes include: Reduced neuropils (region between neuronal cell bodies in the gray matter) and reductions of neurons. Nneuroimaging data > progressive loss of cortical grey matter in schizophrenia . Postmortem studies: markers of apoptosis and levels of apoptotic proteins indicate > increased apoptotic vulnerability.

41 Glutamate and Neurodegenerative Model of Schizophrenia
Again glutamate is the main factor involved in apoptosis (Stahl, 2009): High concentrations of glutamate accumulate in the brain are thought to be involved in the aetiology of a number of neurodegenerative disorders including Alzheimer's disease (Coyle & Puttfarcken, 1993; Lipton & Rosenberg, 1994;). A number of invitro studies > at high concentrations, glutamate is a potent neurotoxin capable of destroying neurons by apoptosis (Behl et al. 1995; Zhang & Bhavnani, 2003).

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43 Conclusion of Glutmate role in Schizophrenia
Both glutamate hypoactivity as well as hyperactivity contribute to the pathology of schizophrenia (Stahl, 2009). Gupta & Kulhara (2010) suggested that: Schizophrenia cannot be explained by a single process of development or degeneration. Research evidence exists for degeneration as well as developmental disorders. The glutamatergic hypothesis bridges the gap between development and neurodegeneration in schizophrenia > "three hit hypothesis" (Keshavan, 1999).

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

45 Glutamate Linked Treatments of Schizophrenia:

46 Glutamate Linked Treatments of Schizophrenia:
Three classes of medications: NMDA partial antagonists (early stage schizophrenia) NMDA partial agonists (later stage schizophrenia): Glycine co-agonists Glycine transporters inhibitors NMDA modulators mGlu autoreceptors co-agonists Minocycline

47 (1) NMDA Partial Antagonists: (Stahl, 2009)
To treat excitotoxicity in early stage: PCP and Ketamine: highly schizophrenogenic NMDA partial antagonists e.g. memantine (already used in Alzheimer) Drugs which block presynaptic release of glutamate e.g. Lamotrigine, gabapentin and pregabalin. 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)

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49 NMDA Partial Agonists: glycine co-agonists
To treat glutamate hypofunctioning in later stages of schiz: Chaves et al (2009): the main strategy used in the last two decades has relied on agonists at the allosteric glycine receptor site of the NMDA complex (glycine co-agonists) as a way to avoid causing glutamate neurotoxicity. Two ways to this:

50 Glycine Co-agonists as Partial NMDA Agonists: (Chaves et al, 2009) (Stahl, 2009)
Glycine agonists to activate glycine co-agonist site on the NMDA receptos 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 (b) Glycine transporters inhibitors (GlyT1 inhibitirs): e.g. sarcosine > promising remedy for negative symptoms of schizophrenia

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52 NMDA Modulators mGlu autoreceptors co-agonists
Wieronska and Pilc (2009): mGlu receptors as the ideal target for medication especially if using the mGlu receptors allosteric binding sites (co-agonists) e.g. methionine amide. Mechanisms of action are not quite clear mGluR2/3 are mainly autoreceptors that prevent glutamate release. The final result is enhancing glutamate activity (?).

53 Metabotropic glutamate receptors

54 NMDA Modulators: mGlu2/3 autoreceptors co-agonists
They reverse the effects of PCP and Ketamine in animals (Stahl, 2009) Some studies > methionine amide: effective against + ve and - ve symptoms of schizophrenia (Moghaddam, 2005). A RCT > after four weeks of treatment, an agonist for the mGluR2/3 (LY ) has similar efficacy as Olanzapine in ameliorating positive and negative symptoms of schizophrenia (Patil et al., 2007).

55 NMDA Modulators: Minocycline (Chaves et al, 2009)
second-generation tetracycline with a broad spectrum of antimicrobial activities and anti-inflammatory properties latest studies suggest that it is related to the glutamatergic system: minocycline reversed several NMDA antagonist effects in animal studies and showed good results in the treatment of patients with schizophrenia Has neuroprotective effects in several animal and human models of neurological diseases, including Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and ischemia

56 Comments Glutamate hypothesis is a welcome addition but it is not well developed yet, many issues need clarification e.g. Interactions between glutamte system, glycine system, monoamines and other systems. Usage of glutamte kinked drugs in treatment of schizophrenia and possible effects on depression, anxiety, epilepsy, etc Glutamte excitotoxicity and NMDA hypofunctioning in schizophrenia is not clear Why mGlu2/3R agonists can enhance glutamate activities despite of the fact that they should be reducing the release of glutamate? Why Glutamate linked drugs are only used as augmentation with atypical antipsychotic drugs? We need to avoid the dopamine mistake: Could it be over simplistic to attribute a major illness to the mere quantitative increase or decrease of one chemical transmitter? Could it be over simplistic to assume that schizophrenia is a one illness with a one neurochemical pathology. 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) rather than schizophrenia theory. This would be similar to the argument that dopamine theory is a theory of psychosis not of schizophrenia?

57 Clinical Questions Side effects and secondary effects of already present Antiglutamatergic drugs on mental illnesses e.g. Drugs which block presynaptic release of glutamate e.g. Lamotrigine, gabapentin and pregabalin, can they cause deterioration of schizophrenia? Can GABA-ergic drugs like sodium valproate be a better choice in schizophrenia?

58 Thank you


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