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: 3.94). 03/2012; 25(2):96-102. DOI: 10.1097/YCO.0b013e32835035b2
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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- "The results of these studies, although inconclusive, most indicate beneficial effects of augmentation of antipsychotic therapy, also in the negative and cognitive symptomatology (Buchanan et al., 2007b, Singh and Singh, 2011, Umbricht et al., 2014). Sarcosine (N-methylglycine) used in our project is an exogenous amino acid, which is a natural inhibitor of the glycine receptor and the source of glycine (Kantrowitz and Javitt, 2012). The purpose of sarcosine adding was to improve mental state, overall functioning and quality of life of patients. "
ABSTRACT: This study was undertaken with the purpose to determine if there are changes in metabolic parameters during 6-month add-on treatment with sarcosine in patients with schizophrenia. This was a randomized double blind, placebo-controlled and parallel group study. Eligible participants were randomly assigned to receive 2 g of sarcosine (n=30) or placebo (n=29). Sarcosine was administered as supplementation to the ongoing antipsychotic treatment. Augmentation with sarcosine had no effect on any of the analyzed cardiometabolic parameters. Also, augmentation with sarcosine had no effect on any of the analyzed body composition parameters. This is the first randomized placebo-controlled study to examine the metabolic safety of sarcosine in patients with schizophrenia. Clinically, this observation is of high importance considering how prevalent are metabolic abnormalities in patients with schizophrenia.
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- "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. "
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.
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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 "
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.
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