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N-methyl-d-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, d-serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of d-amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases d-serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications. [ABSTRACT FROM AUTHOR]

Correction to: Neurochemical Research https://doi.org/10.1007/s11064-023-03956-2 The article "Luvadaxistat: A Novel Potent and Selective d-Amino Acid Oxidase Inhibitor Improves Cognitive and Social Defcits in Rodent Models for Schizophrenia", written by Rosa Fradley, Pascal Goetghebeur, David Miller, Russell Burley, Sarah Almond, Agnès Gruart i Massó, José M. Delgado García, Bin Zhu, Eimear Howley, Jo C. Neill, Ben Grayson, Philip Gaskin, Mark Carlton, Ian Gray, Jordi Serrats, and Ceri H. Davies, was originally published electronically on the publisher's internet portal (https://link.springer.com/article/10.1007/s11064-023-03956-2) on 8 June 2023 without open access. The original article can be found online at https://doi.org/10.1007/s11064-023-03956-2. [Extracted from the article]

Abstract: Schizophrenia is a chronic and debilitating disease which is thought to arise from a neuro-developmental disorder. Both the stable tubule-only polypeptide (STOP) protein and the N-methyl-d-aspartate (NMDA) NR1 subunit are involved in neuronal development and physiology. It has therefore been postulated that transgenic mice lacking either the STOP or the NMDAR1 gene would show a ‘schizophrenic-like’ phenotype. Here, STOP knockout and NMDA NR1 hypomorphic mice were assessed in a behavioural measure that can be used to detect schizophrenic-like phenotypes: a change in sensorimotor gating, measured through prepulse inhibition (PPI). STOP knockout mice were further assessed in another measure of ‘schizophrenic-like behaviour’: hyperlocomotion. The PPI deficit exhibited by both the STOP knockout and NMDA knockdown mice could not be reversed by acute treatment with the atyptical antipsychotic, clozapine (1mg/kg, i.p.) but the hyperlocomotion shown by the STOP knockout mice was reversed with the same acute dose of clozapine. [Copyright &y& Elsevier]