Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Disturbances in glutamate transmission and NMDA receptor hypofunction are associated with schizophrenia. The NMDA receptor hypofunction hypothesis proposes that reduced NMDA receptor activity leads to increased mesolimbic dopamine activity causing positive symptoms and reduced mesocortical dopamine causing negative and cognitive symptoms. Several clinical studies have explored using NMDA agonists and drugs targeting downstream glutamate release as adjunctive treatments for schizophrenia with some success in improving symptoms. Ongoing research continues to develop new glutamatergic drugs for treating schizophrenia.
1. Glutamate & Schizophrenia
Azimatul Karimah
Corresponding address : oe_tjie@yahoo.com
Asian Congress of Schizophrenia Research (ACSR), Bali 2013
2. Glutamate
• the major excitatory transmitter in the mammalian
central nervous system (CNS)
(Collingridge and Singer, 1990; Danysz et al., 1995; Collingridge and Bliss, 1995; Stone, 2011)
• sensitive to glutamate kills neurons through receptor-mediated
depolarization and calcium influx
(Obrenovitch and Urenjak, 1997; Parsons et al., 1998).
Excitotoxicity
(Rothman and Olney, 1987)
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6. Glutamatergic Dysfunction
• schizophrenia, anxiety, depression (Danysz et al., 1995; Parsons et al.,
1998)
• associated with long term plastic changes in the CNS
chronic pain, drug tolerance, dependence, addiction,
partial complex seizures and tardive dyskinesia (Danysz et
al., 1995; Trujillo and Akil, 1995; Dickenson, 1997; Parsons et al., 1998).
• NMDA receptors regulate dopamine neurons
• the hypofunction of NMDA receptors abnormal
dopamine activity symptoms of schizophrenia
Stahl, 2007
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7. Disturbance of glutamate
Disturbance of glutamate
the neurotoxic potential of endogenous glutamate
- increase in glutamate release,
- malfunctioning of neuronal and glial uptake,
- energy deficits
- neuronal depolarization,
- changes in glutamate receptor properties or expression patterns
- free radical formation,
- the presence of toxic proteins (ß-amyloid and tau in Alzheimer)
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8. Glutamate-Dopamine Interaction
Ketamine, PCP
(glutamate antagonist)
Amphetamine
(dopamine agonist)
Positive
symptoms
Negative
symptoms
Cognitive
symptoms
1. Dopaminergic dysregulation may be “downstream” of
a primary deficit in NMDA function ???
2. Cognitive and negative symptoms arise from
abnormalities NMDA receptor ?
-Uci- (Javitt, 2010, Stone, 2011)
9. Hypothesis of Schizophrenia
The NMDA Receptor Hypofunction
• Hypoactivity NMDA in VTA can not inhibit mesolimbic
dopamine neurons positive symptoms
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10. Hypothesis of Schizophrenia (2)
The NMDA Receptor Hypofunction
• NMDA receptor hypoactivity lose excitatory drive in mesocortical
dopamine neurons negative, cognitive and affective symptoms
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11. Clinical Studies with NMDA Agonist
• 1st Generation : glycine modulatory site of the NMDA
receptor
• 2nd generation : glycine type I (GlyT1) transport
inhibitors (GTIs)
Javitt, 2010
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12. Clinical Studies with NMDA Agonist
• Redox-sensitive site modulated by glutathione (GSH) N-acetylcysteine,
GSH precursor
• Pathological glutamate release compounds that inhibit
presynaptic glutamate release may also be therapeutic
Javitt, 2010
(2)
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13. Result in Clinical Studies
Clinical trials Full NMDA Agonist (Glycine) + Antipsychotic
(Javitt, 2010)
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14. Reduction of downstream
glutamate release
Lamotrigine
• Adjunctive treatment
• reverse positive, negative and cognitive symptoms
associated with ketamine administration in healthy
volunteers [Hosak and Libiger, 2002]
• an add-on medication for patients who are only
partially responsive to clozapine, in modest effect
[Tiihonen et al. 2009].
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15. Reduction of downstream
glutamate release (2)
mGlu2/3 receptor agonist (LY2140023)
• Agonist inhibit synaptic glutamate release NMDA
recepor antagonist [Javitt, 2004;Moghaddam, 2004]
- Improvement positive and negative symptoms vs
placebo (Patil et al, 2007)
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16. Reduction of downstream
glutamate release (3)
mGlu2/3 receptor agonist (LY2140023)
• Vs Olanzapine 15mg daily, no significant difference of
response to positive and negative symptoms
• No elevated prolactin, weight gain or EPS
• AE : affective lability, mild reduction of body weigh and
BMI, convulsions occurred in 3 out of the 669 patients
recruited [Kinon et al. 2010].
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17. Reduction of downstream
glutamate release (4)
mGlu2/3 agonists
• work primarily through dopaminergic mechanisms [Seeman
and Guan, 2009].
• downstream effects reducing D2 High expression [Seeman
et al. 2009].
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18. Reduction of downstream
glutamate release (5)
Topiramate
• Adjunctive treatment [Tiihonen et al. 2005]
• AMPA Antagonist by enhancing GABA transmission
• AMPA antagonism only occurs at higher concentrations
[Gibbs et al. 2000].
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19. Other Mechanism
Mynocycline
• inhibit the effects of NMDA receptor antagonism on rats
[Levkovitz et al. 2007; Zhang et al. 2007]
• reverse PCP-induced cognitive deficits [Fujita et al. 2008].
• A double-blind, randomized controlled trial as add-on
treatment in early phase schizophrenia (< 5 year)
revealed a significant effect on negative and cognitive
symptoms [Levkovitz et al. 2010].
• Uncertained mechanism, the inhibition of glutamate
excitotoxicity [Pi et al. 2004; Wilkins et al. 2004].
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20. Other Mechanism (2)
Canabidiol (CBD)
• a modulatory effect on glutamatergic transmission, [Long
et al. 2006; Moreira and Guimaraes, 2005,[Hallak et al. 2011]
• acute intoxication with cannabis
low CBD = impairments in recall,
high CBD did not induce any cognitive deficits
[Morgan et al. 2010]
• Effective as an antipsychotic in patients with
schizophrenia, no additional beneficial effect in a
small open-label study of clozapine-resistant patients
[Zuardi et al. 2006]
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22. Conclussion
• Glutamatergic pathway is known as one mechanism on
developing psychopathology of schizophrenia
• The mechanism associates indirectly with other
neurotransmitter systems such as dopamine and GABA
• Until now, there are many studies of developing
glutamatergic agent for treating schizophrenia that
would be promising in the future
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Notas del editor
Reseptor ini terkait dengan kanal ion bagi ion Na dan Ca
memiliki afinitas terhadap ion Mg++ Akibatnya ion Mg++ dapat
mengikat reseptor NMDA dan memblokade kanal yang sedianya
akan dilewati oleh ion Na+ atau Ca++.
Tetapi jika terjadi depolarisasi, afinitas Mg++ dengan reseptor
tersebut menjadi berkurang Mg++ akan terlepas dan kanal tidak
lagi terblokade Karena itu, aktivitas reseptor NMDA memerlukan
reseptor lain untuk menginisiasi aktivasinya, yaitu reseptor glutamat
non-NMDA
An important descending glutamatergic pathway projects from cortical pyramidal neurons to dopamine neurons in the ventral tegemental area (Figure 3A, left panel). This descending cortico-brainstem glutamate pathway normally acts as a brake on the mesolimbic dopamine pathway. It does this by communicating with these dopamine neurons through an inhibitory γ-aminobutyric acid interneuron in the ventral tegmental area (VTA) (Figure 3A, left panel). This normally results in tonic inhibition of dopamine release from the mesolimbic pathway. However, if NMDA receptors in the VTA are hypoactive in untreated schizophrenia, and thus cannot do their job of tonically inhibiting mesolimbic dopamine neurons, this would cause mesolimbic dopamine hyperactivity and the positive symptoms of psychosis
cortico-brainstem glutamate neurons synapse directly upon those dopamine neurons in the VTA that project to the cortex, those so-called mesocortical dopamine neurons (Figure 4A, left panel). This means that cortico-brainstem glutamate neurons normally function as accelerators of these mesocortical dopamine neurons and, therefore, they tonically excite them (Figure 4A, left panel). The consequence of this neuronal circuitry is that when cortico-brainstem projections to mesocortical dopamine neurons have NMDA receptor hypoactivity, they lose their excitatory drive and become hypoactive, as shown in Figure 4B (right panel). This could hypothetically explain why mesocortical dopamine neurons are hypoactive. Thus, their link to the cognitive, negative, and affective symptoms of schizophrenia shown in Figure 4B (right panel).
An important descending glutamatergic pathway projects from cortical pyramidal neurons to dopamine neurons in the ventral tegemental area (Figure 3A, left panel). This descending cortico-brainstem glutamate pathway normally acts as a brake on the mesolimbic dopamine pathway. It does this by communicating with these dopamine neurons through an inhibitory γ-aminobutyric acid interneuron in the ventral tegmental area (VTA) (Figure 3A, left panel). This normally results in tonic inhibition of dopamine release from the mesolimbic pathway. However, if NMDA receptors in the VTA are hypoactive in untreated schizophrenia, and thus cannot do their job of tonically inhibiting mesolimbic dopamine neurons, this would cause mesolimbic dopamine hyperactivity and the positive symptoms of psychosis
Studies with naturally occurring compounds to date have primarily used glycine, administered at a dose of up to 800 mg/kg (approx. 60 g/d) (109-112); D-serine, administered at a dose of 30 mg/kg (approx. 2.1 g/d) or D-alanine administered at a dose of 100 mg/kg; and sarcosine, administered at a dose of
30 mg/kg (approx. 2.1 g/d). For glycine, this represents the highest practical dose because of the quantity of amino acid needed to significantly increase
brain glycine levels. For other compounds, formal dose findings studies have not been performed, and maximum tolerated doses are presently unknown
Summary of clinical trials performed to date with
full NMDA agonists combined with antipsychotics other than
clozapine. Studies were conducted using the amino acid glycine
at doses of 0.4-0.8 g/kg (30-60 g/d) unless otherwise indicated.
Further details about individual studies are provided in (83).
CONSIST refers to The Cognitive and Negative Symptoms in
Schizophrenia Trial (132). Statistics were calculated as weighted
average of % change scores for negative symptoms, across trials.
Second, based upon the observation that NMDA blockade leads to rebound increases in glutamate release that may themselves be pathological (96), it has been proposed that compounds that inhibit presynaptic glutamate release may also be therapeutic. Examples of such compounds include the anti-epilepsy drug lamotrigine and agonists of metabotropic glutamate type 2/3 (mGluR2/3) receptors, which are localized to presynaptic glutamate terminals in prefrontal cortex. mGluR2/3 agonists have been shown to be effective in reversing behavioral effects of NMDA antagonists in rodent models (98), supporting the potential efficacy of these compounds as novel antipsychotic agents. In addition, both lamotrigine and mGluR 2/3 agonists have also been shown to reverse clinical effects of ketamine during acute challenge in normal volunteers, further supporting the applicability of basic models to humans. In general, therefore, as the NMDA model reaches its second decade, the base of treatment development based upon glutamatergic theories continues to increase.
Glutamate mGlu 2/3 receptors are presynaptic
autoreceptors [Kew and Kemp, 2005]. Agonists
inhibit synaptic glutamate release (Figure 6), and
have been shown to reduce the effects of NMDA
receptor antagonists, and amphetamine in both
animal and human studies [Javitt, 2004;
Moghaddam, 2004]. A recent phase II trial of an
mGlu2/3 receptor agonist (LY2140023, an oral
prodrug of LY404039), in a sample of patients
with chronic schizophrenia, reported significant
improvement in positive and negative symptoms
compared with placebo [Patil et al. 2007].
Second, based upon the observation that NMDA blockade leads to rebound increases in glutamate release that may themselves be pathological (96), it has been proposed that compounds that inhibit presynaptic glutamate release may also be therapeutic. Examples of such compounds include the anti-epilepsy drug lamotrigine and agonists of metabotropic glutamate type 2/3 (mGluR2/3) receptors, which are localized to presynaptic glutamate terminals in prefrontal cortex. mGluR2/3 agonists have been shown to be effective in reversing behavioral effects of NMDA antagonists in rodent models (98), supporting the potential efficacy of these compounds as novel antipsychotic agents. In addition, both lamotrigine and mGluR 2/3 agonists have also been shown to reverse clinical effects of ketamine during acute challenge in normal volunteers, further supporting the applicability of basic models to humans. In general, therefore, as the NMDA model reaches its second decade, the base of treatment development based upon glutamatergic theories continues to increase.
Glutamate mGlu 2/3 receptors are presynaptic
autoreceptors [Kew and Kemp, 2005]. Agonists
inhibit synaptic glutamate release (Figure 6), and
have been shown to reduce the effects of NMDA
receptor antagonists, and amphetamine in both
animal and human studies [Javitt, 2004;
Moghaddam, 2004]. A recent phase II trial of an
mGlu2/3 receptor agonist (LY2140023, an oral
prodrug of LY404039), in a sample of patients
with chronic schizophrenia, reported significant
improvement in positive and negative symptoms
compared with placebo [Patil et al. 2007].
Other metabotropic ligands, including mGluR5
(101, 102) and mGluR8 (103) agonists, have also
been proposed as potential treatments for schizophrenia,
based upon their ability to modulate NMDA
receptor-mediated neurotransmission (104). Finally,
N-acetylaspartylglutamate (NAAG) may be an endogenous
ligand for mGlu2/3 receptors in CNS. NAAG is
broken down by NAAG peptidase (glutamate carboxypeptidase
II) (105). Compounds that inhibit NAAG
peptidase, such as an experimental inhibitor termed
ZJ43, would therefore lead to increased mGlu2/3 occupancy.
This compound has been tested preclinically and
shown to inhibit PCP- and MK-801-induced behaviors
in animals, consistent with an effect on NMDA receptor-
mediated neurotransmission (106, 107).
Finally, some authors have suggested that NMDA
antagonists may be beneficial, based upon concepts
that cognitive deficits in schizophrenia may result from
hyper-glutamatergic neurotoxicity (13). Examples of
compounds that have been considered based upon
this hypothesis are AMPA antagonists and the anti-
Alzheimers disease drug memantine. To date, however,
clinical experience with NMDA antagonists has not
been encouraging (108).
Other metabotropic ligands, including mGluR5
(101, 102) and mGluR8 (103) agonists, have also
been proposed as potential treatments for schizophrenia,
based upon their ability to modulate NMDA
receptor-mediated neurotransmission (104). Finally,
N-acetylaspartylglutamate (NAAG) may be an endogenous
ligand for mGlu2/3 receptors in CNS. NAAG is
broken down by NAAG peptidase (glutamate carboxypeptidase
II) (105). Compounds that inhibit NAAG
peptidase, such as an experimental inhibitor termed
ZJ43, would therefore lead to increased mGlu2/3 occupancy.
This compound has been tested preclinically and
shown to inhibit PCP- and MK-801-induced behaviors
in animals, consistent with an effect on NMDA receptor-
mediated neurotransmission (106, 107).
Finally, some authors have suggested that NMDA
antagonists may be beneficial, based upon concepts
that cognitive deficits in schizophrenia may result from
hyper-glutamatergic neurotoxicity (13). Examples of
compounds that have been considered based upon
this hypothesis are AMPA antagonists and the anti-
Alzheimers disease drug memantine. To date, however,
clinical experience with NMDA antagonists has not
been encouraging (108).
Studies of other mechanisms also show suggestive findings. Thus, one study of N-acetylcysteine, a precursor of glutathione, produced significant improvement in PANSS total and negative symptoms in schizophrenia , along with improvement in generation of MMN, which may serve as a biomarker of NMDA dysfunction . Two small studies with lamotrigine showed suggestive results, although a subsequent multicenter double-blind study was negative. To date, one phase II study with the oral mGluR2/3 agonist prodrug LY2140023, used as monotherapy in acutely relapsing subjects, showed clinical efficacy similar to that of olanzapine with markedly reduced incidence of metabolic side effects. Although this study requires replication, it is encouraging with regard to overall efficacy of glutamatergic
approaches.