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Antipsychotic treatment modulates glutamate transport and NMDA receptor expression

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Abstract

Schizophrenia patients often suffer from treatment-resistant cognitive and negative symptoms, both of which are influenced by glutamate neurotransmission. Innovative therapeutic strategies such as agonists at metabotropic glutamate receptors or glycin reuptake inhibitors try to modulate the brain’s glutamate network. Interactions of amino acids with monoamines have been described on several levels, and first- and second-generation antipsychotic agents (FGAs, SGAs) are known to exert modulatory effects on the glutamatergic system. This review summarizes the current knowledge on effects of FGAs and SGAs on glutamate transport and receptor expression derived from pharmacological studies. Such studies serve as a control for molecular findings in schizophrenia brain tissue and are clinically relevant. Moreover, they may validate animal models for psychosis, foster basic research on antipsychotic substances and finally lead to a better understanding of how monoaminergic and amino acid neurotransmissions are intertwined. In the light of these results, important differences dependent on antipsychotic substances, dosage and duration of treatment became obvious. While some post-mortem findings might be confounded with multifold drug effects, others are unlikely to be influenced by antipsychotic treatment and could represent important markers of schizophrenia pathophysiology. In similarity to the convergence of toxic and psychotomimetic effects of dopaminergic, serotonergic and anti-glutamatergic substances, the therapeutic mechanisms of SGAs might merge on a yet to be defined molecular level. In particular, serotonergic effects of SGAs, such as an agonism at 5HT1A receptors, represent important targets for further clinical research.

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Conflict of interest

M. Zink has received unrestricted scientific grants of ERAB (European Research Advisory Board), German Research Foundation (DFG), Servier, Pfizer Pharma GmbH, Bristol-Myers Squibb GmbH & CoKGaA, further speaker and travel support from Pfizer Pharma GmbH, Bristol-Myers Squibb, Otsuka, Astra Zeneca, Eli-Lilly, Janssen Cilag, Servier, Trommsdorff and Roche. S. Englisch has received travel expenses and consultant fees from AstraZeneca, Bristol-Myers Squibb GmbH & CoKGaA, Eli-Lilly, Janssen Cilag, Pfizer Pharma, Roche Pharma and Servier. A. Schmitt was honorary speaker for TAD Pharma and Roche and has been member of the Roche advisory board.

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  1. Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, P.O. Box 12 21 20, 68072, Mannheim, Germany

    Mathias Zink & Susanne Englisch

  2. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany

    Andrea Schmitt

  3. Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of São Paulo, São Paulo, Brazil

    Andrea Schmitt

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  1. Mathias Zink
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Zink, M., Englisch, S. & Schmitt, A. Antipsychotic treatment modulates glutamate transport and NMDA receptor expression. Eur Arch Psychiatry Clin Neurosci 264 (Suppl 1), 67–82 (2014). https://doi.org/10.1007/s00406-014-0534-4

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