Abstract
Over the past two decades, increasing evidence from preclinical and human studies supports a major role of glutamatergic dysfunction in the aetiopathology of schizophrenia. Genetic, postmortem and neuroimaging studies in schizophrenia patients showed alterations in different glutamatergic elements. Thus, glutamatergic system has emerged as a promising target for the treatment of schizophrenia, especially for symptoms not addressed by current antipsychotic medications, i.e. negative symptoms and cognitive deficits. To date, several drugs aiming at restoring glutamatergic function in schizophrenia have already been researched. The main pharmacological actions of these drugs comprise (1) potentiation of the NMDA receptor function and (2) activation of metabotropic glutamate receptors (mGluRs). Different glutamatergic targets have been proposed to enhance NMDA functioning, including agonism at the glycine-binding site and inhibition of the glycine transporter (GlyT1). Additionally, agonists of the mGlu2/3 receptor and positive allosteric modulators (PAMs) of mGlu2 receptors have been tested as therapeutic bets for the treatment of schizophrenia. From all emerging glutamatergic drugs in schizophrenia, the selective GlyT1 inhibitor Bitopertin and the orthosteric mGlu2/3 receptor agonist Pomaglumetad methionil have reached Phase III clinical trials. Despite discouraging outcomes from these studies, deeper analyses on their methodological features—including patient selection, previous medications, dosages, etc.—highlight the effectiveness of these compounds in patients with schizophrenia.
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Muguruza, C., Callado, L.F. (2022). Glutamate, Glutamatergic Drugs and Schizophrenia. In: Pavlovic, Z.M. (eds) Glutamate and Neuropsychiatric Disorders. Springer, Cham. https://doi.org/10.1007/978-3-030-87480-3_17
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