Glutamate & schizophrenia
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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.
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Glutamate & 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) -Uci-
- 3. Glutamate Receptors Glutamate receptors Ionotropic (Ion channels) quisqualate a-Amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA) kainate N-methyl-D-aspartate (NMDA). NR1 NR2 NR2A-D NR3 Metabotropic (2nd messenger & cAMP) Group 1 mGluR1/5 Group 2 mGluR2/3 Group 3 mGluR4/6/7/8 POST SYNAPS PRESYNAPS (neuron & glia) (Stone, 2011) -Uci-
- 5. NMDA Receptor Activation -Uci-
- 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 -Uci-
- 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) -Uci-
- 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 -Uci-
- 10. Hypothesis of Schizophrenia (2) The NMDA Receptor Hypofunction • NMDA receptor hypoactivity lose excitatory drive in mesocortical dopamine neurons negative, cognitive and affective symptoms -Uci-
- 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 -Uci-
- 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) -Uci-
- 13. Result in Clinical Studies Clinical trials Full NMDA Agonist (Glycine) + Antipsychotic (Javitt, 2010) -Uci-
- 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]. -Uci-
- 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) -Uci-
- 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]. -Uci-
- 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]. -Uci-
- 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]. -Uci-
- 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]. -Uci-
- 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] -Uci-
- 21. Glutamatergic drugs currently in development for the Treatment of Schizophrenia Stone, 2011 -Uci-
- 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 -Uci-
Editor's Notes
- 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.