Article

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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    • "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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    • "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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