Translating Glutamate: From Pathophysiology to Treatment

Translational Schizophrenia Research Center, Nathan Kline Institute/Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Science translational medicine (Impact Factor: 14.41). 09/2011; 3(102):102mr2. DOI: 10.1126/scitranslmed.3002804
Source: PubMed

ABSTRACT The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders-including schizophrenia, drug abuse and addiction, autism, and depression-that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration-approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine-sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development.

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Available from: Chi Ming Lee, Jul 28, 2015
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    • "Research investigating the clinical effectiveness of glutamate agonists for SCZ, Parkinson's, and obsessive–compulsive disorder (Javitt, 2012) suggests new avenues of pharmacotherapy for negative symptoms in addition to the D2 receptor antagonists currently used to manage psychotic symptoms. Alternatively , the clinical effectiveness of glutamate antagonists, such as ketamine for autism and treatment-resistant depression, has suggested a dynamic role for glutamate in brain across a wide array of psychiatric disorders (Javitt et al., 2011). Importantly, glutamate has been most recently implicated in schizophrenia in the largest genome-wide association study of schizophrenia to date (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). "
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    ABSTRACT: Empirically derived phenotypic measurements have the potential to enhance gene-finding efforts in schizophrenia. Previous research based on factor analyses of symptoms has typically included schizoaffective cases. Deriving factor loadings from analysis of only narrowly defined schizophrenia cases could yield more sensitive factor scores for gene pathway and gene ontology analyses. Using an Irish family sample, this study 1) factor analyzed clinician-rated Operational Criteria Checklist items in cases with schizophrenia only, 2) scored the full sample based on these factor loadings, and 3) implemented genome-wide association, gene-based, and gene-pathway analysis of these SCZ-based symptom factors (final N=507). Three factors emerged from the analysis of the schizophrenia cases: a manic, a depressive, and a positive symptom factor. In gene-based analyses of these factors, multiple genes had q<0.01. Of particular interest are findings for PTPRG and WBP1L, both of which were previously implicated by the Psychiatric Genomics Consortium study of SCZ; results from this study suggest that variants in these genes might also act as modifiers of SCZ symptoms. Gene pathway analyses of the first factor indicated over-representation of glutamatergic transmission, GABA-A receptor, and cyclic GMP pathways. Results suggest that these pathways may have differential influence on affective symptom presentation in schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 03/2015; 164(1-3). DOI:10.1016/j.schres.2015.02.013 · 4.43 Impact Factor
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    • "Such challenges are amplified for disorders involving pediatric populations such as ASD because evaluations of drug engagement on brain molecular targets may not be feasible in pediatric samples and because of reliance on caretaker reports as measures of clinical outcomes. In addition, because relevant molecular targets are parts of complex developmental pathways in pediatric disorders, demonstrating an agent's interaction with a specific receptor does not ensure an effect on relevant network level processing or clinical endpoints (Javitt et al., 2011). The slow pace of novel psychosocial and pharmacological treatment development in ASD may be attributable to a number of factors including (a) the phenotypic and etiological heterogeneity of ASD that makes it exceedingly unlikely that a single treatment will FUTURE RESEARCH IN ASD be effective for all, or even most, individuals with ASD; (b) a diagnosis based on social communication, which is inevitably context dependent and requires extensively trained clinicians to evaluate; (c) a relatively limited understanding of the pathophysiology of ASD and clear relationships between potential etiologies and clinical symptoms; and (d) a lack of well-defined self-report or caregiver-report outcome measures. "
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    ABSTRACT: This article suggests future directions for research aimed at improving our understanding of the etiology and pathophysiology of autism spectrum disorder (ASD) as well as pharmacologic and psychosocial interventions for ASD across the lifespan. The past few years have witnessed unprecedented transformations in the understanding of ASD neurobiology, genetics, early identification, and early intervention. However, recent increases in ASD prevalence estimates highlight the urgent need for continued efforts to translate novel ASD discoveries into effective interventions for all individuals with ASD. In this article we highlight promising areas for ongoing and new research expected to quicken the pace of scientific discovery and ultimately the translation of research findings into accessible and empirically supported interventions for those with ASD. We highlight emerging research in the following domains as particularly promising and pressing: (a) preclinical models, (b) experimental therapeutics, (c) early identification and intervention, (d) psychiatric comorbidities and the Research Domain Criteria initiative, (e) ecological momentary assessment, (f) neurotechnologies, and (g) the needs of adults with ASD. Increased research emphasis in these areas has the potential to hasten the translation of knowledge on the etiological mechanisms of ASD to psychosocial and biological interventions to reduce the burden of ASD on affected individuals and their families.
    Journal of Clinical Child & Adolescent Psychology 09/2014; 43(5):828-843. DOI:10.1080/15374416.2014.945214 · 1.92 Impact Factor
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    • "Diffusion Tensor Imaging (DTI) studies have identified important white matter abnormalities (Kubicki et al., 2007). Further, effective drug development necessitates the identification of biological markers to measure target engagement (Javitt et al., 2011), a task for which neuroimaging is critical. Proton Magnetic Resonance Spectroscopy ( 1 H-MRS) is an MR-based technique that permits researchers to examine metabolites in vivo in the human brain. 1 H-MRS can be used to measure glutamate and its metabolites. "
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    ABSTRACT: The last fifteen years have seen a great increase in our understanding of the role of glutamate in schizophrenia (SCZ). The glutamate hypothesis focuses on disturbances in brain glutamatergic pathways and impairment in signaling at glutamate receptors. Proton Magnetic Resonance Spectroscopy ((1)H-MRS) is an MR-based technique that affords investigators the ability to study glutamate function by measuring in vivo glutamatergic indices in the brains of individuals with SCZ. (1)H-MRS studies have been performed comparing glutamatergic levels of individuals with SCZ and healthy control subjects or studying the effect of antipsychotic medications on glutamatergic levels. In this article we summarize the results of these studies by brain region. We will review the contribution of (1)H-MRS studies to our knowledge about glutamatergic abnormalities in the brains of individuals with SCZ and discuss the implications for future research and clinical care.
    Schizophrenia Research 01/2014; 152(2-3). DOI:10.1016/j.schres.2013.12.013 · 4.43 Impact Factor
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