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Translating the Glutamatergic Hypothesis of Schizophrenia Through Homeostatic Regulation of Brain Glycine

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Psychiatry and Neuroscience Update

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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.

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Acknowledgements

We wish to acknowledge the support from the ETH Zurich and the Swiss National Science Foundation for support of our research on glycine transporter 1. Legacy Research Institute, Portland, Oregon, had provided additional support for the authors during the preparation of this chapter.

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Authors and Affiliations

  1. Institute of Brain and Cognitive Science, NYU Shanghai, 3663 Zhongshan Road North, Shanghai, 20006, China

    Sylvain Dubroqua Ph.D.

  2. Laboratory of Behavioral Neuroscience, Legacy Research Institute, 1225 NE Second Avenue, Portland, OR, 97232, USA

    Philipp Singer Ph.D.

  3. Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong, China

    Benjamin K. Yee D.Phil.

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  1. Sylvain Dubroqua Ph.D.
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  3. Benjamin K. Yee D.Phil.
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Correspondence to Benjamin K. Yee D.Phil. .

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  1. Guaymallen Mendoza, Argentina

    Pascual Ángel Gargiulo

  2. Member of the Council of the Institute of Neurobiology (Buenos Aires); Member of the Board of Certification, National Academy of Medicine (Argentina), Psychiatrist by University Complutense of Madrid and University of Buenos Aires; Former Director of National Institute of Mental Health (Argentina), Cuyo, Buenos Aires, Argentina

    Humberto Luis Mesones Arroyo

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Dubroqua, S., Singer, P., Yee, B.K. (2015). Translating the Glutamatergic Hypothesis of Schizophrenia Through Homeostatic Regulation of Brain Glycine. In: Gargiulo, P., Arroyo, H. (eds) Psychiatry and Neuroscience Update. Springer, Cham. https://doi.org/10.1007/978-3-319-17103-6_25

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