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Title: Translating the glutamatergic hypothesis of schizophrenia through homeostatic regulation of brain glycine
Authors: Dubroqua, S
Singer, P
Yee, BK 
Keywords: Antipsychotic
Glycine transporter
N-methyl-d-aspartate receptor
Issue Date: 2015
Publisher: Springer International Publishing
Source: In PA Gargiulo & HL Mesones-Arroyo (Eds.), Psychiatry and neuroscience update : bridging the divide, p. 353-374. Cham: Springer International Publishing, 2015 How to cite?
Abstract: No effective treatment exists for the negative symptoms and cognitive impairments of schizophrenia. The loss of normal affective and cognitive function severely undermines a patients’ ability to regain independence and social reintegration even when the positive psychotic symptoms have been stabilized by medications that are currently available. The US Food and Drug Administration fully recognizes the need and legitimacy to target negative and cognitive symptoms in drug development. The theoretical consensus that the pathogenesis of these symptoms involves glutamatergic N-methyl-d-aspartate (NMDA) receptor hypofunction has been driving for over three decades the impetus behind the search for feasible pharmacological strategies to improve NMDA receptor function. One promising approach that emerged in recent years is up-regulating brain glycine levels through the blockade of glycine transporter 1 (GlyT1). It is hypothesized that increasing the availability of glycine, the obligatory NMDA receptor co-agonist, near glutamatergic synapses can boost NMDA receptor excitability without the risk of excitotoxicity following direct stimulation of NMDA receptor. This chapter traces the translation of glycine reuptake inhibition therapy through the latest Phase III clinical trials of the potent selective GlyT1 inhibitor, bitopertin, developed by F. Hoffman-La Roche. We will explore the relevant neural mechanisms underlying this new pharmacotherapy, which appears to possess board spectrum efficacy against both positive and negative schizophrenia symptoms. Preclinical evidence suggests that GlyT1 inhibition may modulate multiple neurotransmitter pathways, including mesolimbic dopamine and brain glycinergic inhibition, which may provide new leads for further target refinement.
ISBN: 9783319171036
DOI: 10.1007/978-3-319-17103-6_26
Appears in Collections:Book Chapter

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