Glutamatergic transmission in schizophrenia: From basic research to clinical practice

Schizophrenia Research Institute, Nathan Kline Institute for Psychiatric Research, New York, USA.
Current opinion in psychiatry (Impact Factor: 3.55). 03/2012; 25(2):96-102. DOI: 10.1097/YCO.0b013e32835035b2
Source: PubMed

ABSTRACT Purpose of review: The past 20 years have seen the glutamatergic hypothesis go from theory to phase III trials of novel mechanism antipsychotics. Recent Findings: We review the recent literature on glutamatergic theory, covering assessment and genetic studies, as well as drug development in animals and humans. Summary: Although evidence continues to accumulate in support of glutamate hypotheses, further research continues to be required and interactions with other key systems need to be explored.

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    • "Pharmacological interventions in schizophrenia are currently focused on enhancing the activity of the N-methyl-D-aspartate (NMDA) receptor, one of the subtypes of glutamatergic ionotropic receptors. There are two known options for influencing the NMDA receptor via the glycine site that are currently under clinical investigation; the direct method consists of administration of glycine or another NMDA receptor co-agonist, such as D-cycloserine and D-serine, and the indirect method consists of inhibiting the glycine transporter type I (GlyT1) with sarcosine, RG1678 (bitopertin), or ALX-5407.6–9 Sarcosine has been used in several small studies,10–14 and the results seem to be promising in treating negative symptoms and cognitive dysfunction where the benefits of known antipsychotics are very limited.15,16 "
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    ABSTRACT: Glutamate is the main excitatory neurotransmitter in the central nervous system. Dysfunction of the glutamatergic system plays an important role in the pathogenesis of schizophrenia. Therefore, glutamatergic agents such as N-methyl-D-aspartate receptor co-agonists (ie, glycine, D-cycloserine) and glycine transporter type 1 inhibitors (eg, sarcosine) are studied for their efficacy in ameliorating negative and cognitive symptomatology in patients with schizophrenia. We report the case of a 23-year-old schizophrenic patient treated with quetiapine and citalopram, who was offered concomitant sarcosine treatment. After obtaining an informed consent, we started administration of 2 g of sarcosine per day to treat persistent negative and cognitive symptoms. The patient's activity and mood improved within 2 weeks, but in the following 2 weeks the patient reported increased drive, activity, libido, unpleasant inner tension, and irritability. We ruled out hypomania and decided to decrease the daily dose of sarcosine to 1 g, which resulted in reduction of drive and irritability. Activity and mood improved compared with his state before adding sarcosine. We suggest a sarcosine dose between 1 g and 2 g per day with an initial dose of 2 g, but if side effects occur, the dose should be decreased to 1 g per day. We would like to emphasize the clinically important glutamate-serotonin interaction during concomitant use of sarcosine, citalopram, and quetiapine in our patient, which may lead to serious discomfort.
    Neuropsychiatric Disease and Treatment 02/2014; 10:263-6. DOI:10.2147/NDT.S54024 · 2.15 Impact Factor
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    • "For example, schizophrenia has been proposed to result from a deficit in forming dynamic links between neuronal populations (the " disconnection " hypothesis; (Friston and Frith, 1995)), and is also linked to neurochemical dysfunction (Carlsson et al., 1999; Lisman et al., 2008; Stephan et al., 2006). There is considerable debate among theorists regarding the relative importance of glutamate and GABA dysfunctions within this disorder (Gonzalez-Burgos and Lewis, 2008; Kantrowitz and Javitt, 2012; Kegeles et al., 2012; Lewis et al., 2005). Importantly, the technique outlined here could be used to directly assess the impact of the relative importance of changes in both transmitter concentrations upon taskrelated changes in neural activity and performance. "
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    ABSTRACT: Frequency specific synchronization of neuronal firing within the gamma-band (30-70Hz) appears to be a fundamental correlate of both basic sensory and higher cognitive processing. In-vitro studies suggest that the neurochemical basis of gamma-band oscillatory activity is based on interactions between excitatory (i.e. glutamate) and inhibitory (i.e. GABA) neurotransmitter concentrations. However, the nature of the relationship between excitatory neurotransmitter concentration and changes in gamma band activity in humans remains undetermined. Here, we examine the links between dynamic glutamate concentration and the formation of functional gamma-band oscillatory networks. Using concurrently acquired event-related magnetic resonance spectroscopy and electroencephalography, during a repetition-priming paradigm, we demonstrate an interaction between stimulus type (object vs. abstract pictures) and repetition in evoked gamma-band oscillatory activity, and find that glutamate levels within the lateral occipital cortex, differ in response to these distinct stimulus categories. Importantly, we show that dynamic glutamate levels are related to the amplitude of stimulus evoked gamma-band (but not to beta, alpha or theta or ERP) activity. These results highlight the specific connection between excitatory neurotransmitter concentration and amplitude of oscillatory response, providing a novel insight into the relationship between the neurochemical and neurophysiological processes underlying cognition.
    NeuroImage 07/2013; 85. DOI:10.1016/j.neuroimage.2013.07.049 · 6.36 Impact Factor
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    • "N-methyl-D-aspartate receptors (NMDAR) are found mainly at excitatory synapses and expressed ubiquitously in the central nervous system (CNS). There is good evidence from clinical, preclinical and theoretical studies that NMDAR are involved in the pathophysiology of several psychiatric diseases (Bergeron and Coyle, 2012; Kantrowitz and Javitt, 2012; Paul and Skolnick, 2003; Schwartz et al., 2012). Indeed, subanesthetic doses of NMDAR antagonists are widely used to model some of the symptoms of schizophrenia (Abi-Saab et al., 1998; Krystal et al., 1994) and over the last decade, they were found clinically useful in the treatment of bipolar depression (Berman et al., 2000). "
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    ABSTRACT: Distinct frequency bands can be differentiated from neuronal ensemble recordings, such as local field potentials or electrocorticogram recordings. Recent years have witnessed a rapid acceleration of research examining how N-methyl-D-aspartate receptor (NMDAR) antagonists influence fundamental frequency bands in cortical and subcortical brain regions. Herein, we systematically review findings from in vivo studies with a focus on delta, theta, gamma and more recently identified high-frequency oscillations. We also discuss some of the current hypotheses that are considered to account for the actions of NMDAR antagonists on these frequency bands. The data emphasize a close relationship between altered oscillatory activity and NMDAR blockade, with both local and large-scale networks accounting for their effects. These findings may have fundamental implications for the psychotomimetic effects produced by NMDAR antagonists.
    Journal of Psychopharmacology 07/2013; 27(11). DOI:10.1177/0269881113495117 · 2.81 Impact Factor
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