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.
"In this work, we follow two lines of evidence concerning the pathogenesis of schizophrenia. First, we consider the n-methyl-d-aspartate (NMDA) glutamate receptor dysfunction hypothesis, which pertains to biological correlates of hypofrontality (Coyle, 2004; Kantrowitz and Javitt, 2012; Olney et al., 1999). Secondly, we consider the membrane lipid hypothesis (Horrobin et al., 1994) that assumes deficient generation or excessive breakdown of membrane phospholipids as a causative pathology in schizophrenia, and that is based on evidence of disturbed membrane lipid turnover in specific brain regions of schizophrenic patients. "
[Show abstract][Hide abstract] ABSTRACT: Glutamatergic dysfunction and altered membrane lipid and energy metabolism have been repeatedly demonstrated in the frontal/prefrontal and anterior cingulate cortex (ACC) in schizophrenia. Though having been already studied in animals, the presumed link between glutamatergic function and structural plasticity has not been investigated directly in the human brain yet. We measured glutamate (Glu), focal energy metabolism, and membrane phospholipid turnover to investigate main pathologies in those key brain regions of schizophrenia.
Schizophrenia Research 08/2015; DOI:10.1016/j.schres.2015.07.013 · 3.92 Impact Factor
"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 "
[Show abstract][Hide abstract] 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.
"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. "
[Show abstract][Hide abstract] 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.
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